Pharmaceutical combination for use in glycemic control in diabetes type 2 patients

ABSTRACT

The present invention refers to a pharmaceutical combination for use in glycemic control in diabetes type 2 patients.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.13/595,590 filed on Aug. 27, 2012, which claims priority from EuropeanPatent Application No. 11179149.7 filed Aug. 29, 2011, the disclosuresof which are incorporated herein by reference in their entirety.

DESCRIPTION

Subject of the present invention is a pharmaceutical combination for usein glycemic control in diabetes type 2 patients, said combinationcomprising (a) desPro³⁶Exendin-4(1-39)-Lys₆-NH₂ (AVE0010, lixisenatide)or/and a pharmaceutically acceptable salt thereof, and (b) a glitazoneor/and a pharmaceutically acceptable salt thereof.

In a healthy person the release of insulin by the pancreas is strictlycoupled to the concentration of blood glucose. An increased level ofblood glucose, as appears after meals, is rapidly counterbalanced by arespective increase in insulin secretion. In fasting condition theplasma insulin level drops to a basal value which is sufficient toensure the continuous supply of glucose to insulin-sensitive organs andtissues and to keep the hepatic glucose production at a low level atnight.

In contrast to diabetes type 1, there is not generally a lack of insulinin diabetes type 2 but in many cases, particularly in progressive cases,the treatment with insulin is regarded as the most suitable therapy, ifrequired in combination with orally administered anti-diabetic drugs.

An increased glucose level in the blood over several years withoutinitial symptoms represents a significant health risk. It could clearlybe shown by the large-scale DCCT study in the USA (The Diabetes Controland Complications Trial Research Group (1993) N. Engl. J. Med. 329,977-986) that chronically increased levels of blood glucose are a mainreason for the development of diabetes complications. Examples fordiabetes complications are micro and macrovascular damages that possiblymanifest themselves in retinopathies, nephropathies or neuropathies andlead to blindness, renal failure and the loss of extremities and areaccompanied by an increased risk of cardiovascular diseases. It can thusbe concluded that an improved therapy of diabetes primarily has to aimkeeping blood glucose in the physiological range as closely as possible.

A particular risk exists for overweight patients suffering from diabetestype 2, e.g. patients with a body mass index (BMI)≥30. In these patientsthe risks of diabetes overlap with the risks of overweight, leading e.g.to an increase of cardiovascular diseases compared to diabetes type 2patients being of a normal weight. Thus, it is particularly necessary totreat diabetes in these patients while reducing the overweight.

Glitazones (also termed thiazolidinediones) such as pioglitazone areantihyperglycemic agents that reduce insulin resistance by sensitizingmuscle, liver and adipose tissue (Dormandy et al., Lancet 2005,366:1270-89, Yki-Jarvinen, N Engl J Med 2004, 351: 1106-18).

Metformin is a biguanide hypoglycemic agent used in the treatment ofnon-insulin-dependent diabetes mellitus (diabetes mellitus type 2) notresponding to dietary modification. Metformin improves glycemic controlby improving insulin sensitivity and decreasing intestinal absorption ofglucose. Metformin is usually administered orally. However, controldiabetes mellitus type 2 in obese patients by metformin may beinsufficient. Thus, in these patients, additional measures forcontrolling diabetes mellitus type 2 may be required.

The compound desPro³⁶Exendin-4(1-39)-Lys₆-NH₂ (AVE0010, lixisenatide) isa derivative of Exendin-4. Lixisenatide is disclosed as SEQ ID NO:93 inWO 01/04156:

SEQ ID NO: 1: Lixisenatide (44 AS)H-G-E-G-T-F-T-S-D-L-S-K-Q-M-E-E-E-A-V-R-L-F-I-E-W-L-K-N-G-G-P-S-S-G-A-P-P-S-K-K-K-K-K-K-NH2SEQ ID NO: 2: Exendin-4 (39 AS)H-G-E-G-T-F-T-S-D-L-S-K-Q-M-E-E-E-A-V-R-L-F-I-E-W-L-K-N-G-G-P-S-S-G-A-P-P-P-S-NH2

Exendins are a group of peptides which can lower blood glucoseconcentration. The Exendin analogue lixisenatide is characterised byC-terminal truncation of the native Exendin-4 sequence. Lixisenatidecomprises six C-terminal lysine residues not present in Exendin-4.

In the context of the present invention, lixisenatide includespharmaceutically acceptable salts thereof. The person skilled in the artknows pharmaceutically acceptable salts of lixisenatide. A preferredpharmaceutically acceptable salt of lixisenatide employed in the presentinvention is acetate.

In the Example of the present invention, it has been demonstrated indiabetes type 2 patients that lixisenatide in an add-on therapy to aglitazone significantly improved glycemic control:

-   -   Lixisenatide in combination with pioglitazone (“lixisenatide        group”) significantly decreased the fasting plasma glucose        compared to the pioglitazone group (“placebo group”) from        baseline to Week 24.    -   In the lixisenatide group, the HbA1c values were significantly        decreased compared to the placebo group from baseline to Week        24.    -   In the lixisenatide group, the percentages of patients reaching        HbA_(1c) values <6.5% or <7% at Week 24 were significantly        higher than in the placebo group.    -   The fasting plasma insulin concentration was lower in the        lixisenatide group, compared to the placebo group.

One aspect of the present invention is a pharmaceutical combination,said combination comprising

-   -   (a) desPro³⁶Exendin-4(1-39)-Lys₆-NH₂ or/and a pharmaceutically        acceptable salt thereof, and    -   (b) a glitazone or/and a pharmaceutically acceptable salt        thereof.

The combination of the present invention can be used for the treatmentof diabetes type 2 patients, or/and for the treatment of conditionsassociated with diabetes type 2. Such conditions include a decrease ofglucose tolerance, an increased postprandial plasma glucoseconcentration, an increase in fasting plasma glucose concentration, anincreased HbA1c value, or/and an increased fasting plasma insulinconcentration.

A preferred aspect of the present invention is a pharmaceuticalcombination for use in glycemic control in diabetes type 2 patients,said combination comprising

-   -   (a) desPro³⁶Exendin-4(1-39)-Lys₆-NH₂ or/and a pharmaceutically        acceptable salt thereof, and    -   (b) a glitazone or/and a pharmaceutically acceptable salt        thereof.

As demonstrated by the Example of the present invention, the combinationas described herein can be used for improving glycemic control. In thepresent invention, “improvement of glycemic control” or “glycemiccontrol” in particular refers to improvement of glucose tolerance,improvement of postprandial plasma glucose concentration, improvement offasting plasma glucose concentration, improvement of the HbA1c valueor/and improvement of fasting plasma insulin concentration.

In particular, improvement of glucose tolerance includes improvement ofthe postprandial plasma glucose concentration or/and improvement offasting plasma insulin concentration. More particular, improvement ofglucose tolerance includes improvement of the postprandial plasmaglucose concentration.

In particular, improvement of postprandial plasma glucose concentrationis reduction of the postprandial plasma glucose concentration. Reductionmeans in particular that the plasma glucose concentration reachesnormoglycemic values or at least approaches these values.

In particular, improvement of fasting plasma glucose concentration isreduction of the fasting plasma glucose concentration. Reduction meansin particular that the plasma glucose concentration reachesnormoglycemic values or at least approaches these values.

In particular, improvement of the HbA1c value is reduction of the HbA1cvalue. Reduction of the HbA1c value in particular means that the HbA1cvalue is reduced below 6.5% or 7%, for example after treatment for atleast one month, at least two months, at least three months, at leastfour months, at least five months, at least six months or at least oneyear.

In particular, improvement of fasting plasma insulin concentration isreduction of fasting plasma insulin concentration. The plasma insulinconcentration is coupled to the plasma glucose concentration. Undertreatment as described herein, in fasting condition the plasma insulinmay reach or at least approach values to ensure the continuous supply ofglucose to insulin-sensitive organs and tissues or/and to keep thehepatic glucose production at a low level at night. At fastingconditions, the insulin concentration may reach or at least approachvalues associated with normoglycemia or plasma glucose concentrationapproaching normoglycemia.

In the context of the present invention, “glitazone”, as used herein,includes pharmaceutically acceptable salts thereof. The glitazone may beselected from pioglitazone, troglitazone, rosiglitazone, andpharmaceutically acceptable salts thereof.

In the present invention, the glitazone, in particular pioglitazone, maybe administered orally. The skilled person knows formulations of theglitazone, in particular pioglitazone, suitable for treatment ofdiabetes type 2 by oral administration. Pioglitazone may be administeredto a patient in need thereof, in an amount sufficient to induce atherapeutic effect. The glitazone, in particular pioglitazone, may beadministered in a dose of at least 10 mg/day, at least 20 mg/day, atleast 30 mg/day, or at least 40 mg/day. The maximal daily dose of theglitazone, in particular pioglitazone, may be 50 mg/day or 60 mg/day. Apreferred dosing range is 10 mg/day to 50 mg/day or 30 mg/day to mg/day.A more preferred dose is about 30 mg/day. For oral administration, theglitazone, in particular pioglitazone, may be formulated in a soliddosage form, such as a tablet or pill. The glitazone, in particularpioglitazone, may be formulated with suitable pharmaceuticallyacceptable carriers, adjuvants, or/and auxiliary substances.

The pharmaceutical combination of the present invention may furthercomprise metformin or/and a pharmaceutically acceptable salt thereof.Metformin is the international nonproprietary name of1,1-dimethylbiguanide (CAS Number 657-24-9). In the present invention,the term “metformin” includes any pharmaceutically acceptable saltthereof.

In the present invention, metformin may be administered orally. Theskilled person knows formulations of metformin suitable for treatment ofdiabetes type 2 by oral administration. Metformin may be administered toa patient in need thereof, in an amount sufficient to induce atherapeutic effect. Metformin may be administered in a dose of at least1.0 g/day or at least 1.5 g/day. For oral administration, metformin maybe formulated in a solid dosage form, such as a tablet or pill.Metformin may be formulated with suitable pharmaceutically acceptablecarriers, adjuvants, or/and auxiliary substances.

If metformin is present in the combination of the present invention,metformin and the glitazone, in particular pioglitazone, may be providedin one formulation, for example in a solid dosage form, such as a tabletor pill. Metformin and the glitazone, in particular pioglitazone, may beformulated with suitable pharmaceutically acceptable carriers,adjuvants, or/and auxiliary substances.

In the present invention, desPro³⁶Exendin-4(1-39)-Lys₆-NH₂ or/and apharmaceutically acceptable salt may be administered in an add-ontherapy to administration of the glitazone, in particular pioglitazone.

In the present invention, the terms “add-on”, “add-on treatment”,“add-on therapy” and “on top of” relate to treatment of diabetesmellitus type 2 with the glitazone, in particular pioglitazone, andlixisenatide. Also included may be the treatment with metformin, asdisclosed herein. The glitazone, in particular pioglitazone, andlixisenatide may be administered within a time interval of 24 h. Theglitazone, in particular pioglitazone, and lixisenatide each may beadministered in a once-a-day-dosage. The glitazone, in particularpioglitazone, and lixisenatide may be administered by differentadministration routes. The glitazone, in particular pioglitazone, may beadministered orally, and lixisenatide may be administered parenterally.

The patient to be treated by the medicament of the present invention maybe a patient suffering from diabetes type 2. The Example demonstrates inthese patients, that administration of lixisenatide in combination withthe glitazone, in particular pioglitazone, provides an advantageoustherapy.

The patient to be treated by the medicament of the present inventionsuffering from diabetes type 2 may be a patient suffering from diabetestype 2, wherein diabetes type 2 is not adequately controlled bytreatment with the glitazone, in particular pioglitazone, alone, forinstance with a dose selected from the range of 10 mg/day to 50 mg/day,in particular about 30 mg/day, for at least 2 or at least 3 months. Inthe present invention, a patient the diabetes type 2 of which is notadequately controlled may have a HbA1c value in the range of 7% to 10%.

The patient to be treated by the medicament of the present inventionsuffering from diabetes type 2 may be an obese patient. In the presentinvention, an obese patient may have a body mass index of at least 30kg/m².

The patient to be treated by the medicament of the present inventionsuffering from diabetes type 2 may have a normal body weight. In thepresent invention, a patient having normal body weight may have a bodymass index in the range of 17 kg/m² to 25 kg/m², 17 kg/m² to <30 kg/m²or <30 kg/m².

The patient to be treated by the medicament of the present invention maybe an adult patient. The patient may have an age of at least 18 years ofmay have an age in the range of 18 to 80 years, of 18 to 50 years, or 40to 80 years, or 50 to 60 years. The patient may be younger than 50years.

The patient to be treated by the medicament of the present inventionpreferably does not receive an antidiabetic treatment, for instance byinsulin or/and related compounds.

The patient to be treated by the medicament of the present invention maysuffer from diabetes mellitus type 2 for at least 1 year or at least 2years. In particular, in the diabetes type 2 patient, diabetes mellitustype 2 has been diagnosed at least 1 year or at least 2 years beforeonset of therapy by the medicament of the present invention.

The diabetes type 2 patient may have a HbA1c value of at least about 8%or at least about 7.5%. The patient may also have a HbA1c value of about7% to about 10%. The example of the present invention demonstrates thattreatment by lixisenatide results in a reduction of the HbA1c value indiabetes type 2 patients.

In yet another aspect of the present invention, the combination asdescribed herein can be used for improving the HbA1c value in a patientsuffering from diabetes type 2, as described herein.

In yet another aspect of the present invention, the combination asdescribed herein can be used for improving glucose tolerance in apatient suffering from diabetes type 2, as described herein.

In yet another aspect of the present invention, the combination asdescribed herein can be used for improving postprandial plasma glucoseconcentration in a patient suffering from diabetes type 2, as describedherein.

In yet another aspect of the present invention, the combination asdescribed herein can be used for improving fasting plasma glucoseconcentration in a patient suffering from diabetes type 2, as describedherein.

In yet another aspect of the present invention, the combination asdescribed herein can be used for improving fasting plasma insulinconcentration in a patient suffering from diabetes type 2, as describedherein.

In the present invention, normoglycemic values are blood glucoseconcentrations of in particular 60-140 mg/dl (corresponding to 3,3 bis7.8 mM/L). This range refers in particular to blood glucoseconcentrations under fasting conditions or/and postprandial conditions.

The diabetes type 2 patient may have a 2 hours postprandial plasmaglucose concentration of at least 10 mmol/L, at least 12 mmol/L, or atleast 14 mmol/L. These plasma glucose concentrations exceednormoglycemic concentrations.

The diabetes type 2 patient may have a glucose excursion of at least 2mmol/L, at least 3 mmol/L, at least 4 mmol/L or at least 5 mmol/L. Inthe present invention, the glucose excursion is in particular thedifference of the 2 hours postprandial plasma glucose concentration andthe plasma glucose concentration 30 minutes prior to a meal test.

“Postprandial” is a term that is well known to a person skilled in theart of diabetology. The term “postprandial” describes in particular thephase after a meal or/and exposure to glucose under experimentalconditions. In a healthy person this phase is characterised by anincrease and subsequent decrease in blood glucose concentration. Theterm “postprandial” or “postprandial phase” typically ends up to 2 hafter a meal or/and exposure to glucose.

The diabetes type 2 patient as disclosed herein may have a fastingplasma glucose concentration of at least 8 mmol/L, at least 8.5 mmol/Lor at least 9 mmol/L. These plasma glucose concentrations exceednormoglycemic concentrations.

In the present invention, desPro³⁶Exendin-4(1-39)-Lys₆-NH₂ or/and thepharmaceutically acceptable salt thereof may be administered to apatient in need thereof, in an amount sufficient to induce a therapeuticeffect.

In the present invention, desPro³⁶Exendin-4(1-39)-Lys₆-NH₂ or/and thepharmaceutically acceptable salt thereof may be formulated with suitablepharmaceutically acceptable carriers, adjuvants, or/and auxiliarysubstances.

The compound desPro³⁶Exendin-4(1-39)-Lys₆-NH₂ or/and a pharmaceuticallyacceptable salt thereof may be administered parenterally, e.g. byinjection (such as by intramuscular or by subcutaneous injection).Suitable injection devices, for instance the so-called “pens” comprisinga cartridge comprising the active ingredient, and an injection needle,are known. The compound desPro³⁶Exendin-4(1-39)-Lys₆-NH₂ or/and apharmaceutically acceptable salt thereof may be administered in asuitable amount, for instance in an amount in the range of 10 to 15 μgper dose or 15 to 20 μg per dose.

In the present invention, desPro³⁶Exendin-4(1-39)-Lys₆-NH₂ or/and apharmaceutically acceptable salt thereof may be administered in a dailydose in the range of 10 to 20 μg, in the range of 10 to 15 μg, or in therange of 15 to 20 μg. DesPro³⁶Exendin-4(1-39)-Lys₆-NH₂ or/and apharmaceutically acceptable salt thereof may be administered by oneinjection per day.

In the present invention, desPro³⁶Exendin-4(1-39)-Lys₆-NH₂ or/and apharmaceutically acceptable salt thereof may be provided in a liquidcomposition. The skilled person knows liquid compositions oflixisenatide suitable for parenteral administration. A liquidcomposition of the present invention may have an acidic or a physiologicpH. An acidic pH preferably is in the range of pH 1-6.8, pH 3.5-6.8, orpH 3.5-5. A physiologic pH preferably is in the range of pH 2.5-8.5, pH4.0-8.5, or pH 6.0-8.5. The pH may be adjusted by a pharmaceuticallyacceptable diluted acid (typically HCl) or pharmaceutically acceptablediluted base (typically NaOH).

The liquid composition comprising desPro³⁶Exendin-4(1-39)-Lys₆-NH₂or/and a pharmaceutically acceptable salt thereof may comprise asuitable preservative. A suitable preservative may be selected fromphenol, m-cresol, benzyl alcohol and p-hydroxybenzoic acid ester. Apreferred preservative is m-cresol.

The liquid composition comprising desPro³⁶Exendin-4(1-39)-Lys₆-NH2or/and a pharmaceutically acceptable salt thereof may comprise atonicity agent. A suitable tonicity agent may be selected from glycerol,lactose, sorbitol, mannitol, glucose, NaCl, calcium or magnesiumcontaining compounds such as CaCl₂. The concentration of glycerol,lactose, sorbitol, mannitol and glucose may be in the range of 100-250mM. The concentration of NaCl may be up to 150 mM. A preferred tonicityagent is glycerol.

The liquid composition comprising desPro³⁶Exendin-4(1-39)-Lys₆-NH2or/and a pharmaceutically acceptable salt thereof may comprisemethionine from 0.5 μg/mL 20 μg/mL, preferably from 1 μg/mL to 5 μg/mL.Preferably, the liquid composition comprises L-methionine.

Yet another aspect of the present invention refers to a method oftreatment of a medical indication, as described herein. For example, themethod may comprise the administration of the combination as describedherein. The method may be a method of treatment of diabetes type 2patients, or/and of treatment of conditions associated with diabetestype 2, as described herein. The patient may be a patient as definedherein.

A further aspect of the present invention is a method for improvement ofglycemic control in diabetes type 2 patients, said method comprisingadministering desPro³⁶Exendin-4(1-39)-Lys₆-NH2 or/and a pharmaceuticallyacceptable salt thereof, in combination with a glitazone, in particularpioglitazone, to a patient in need thereof. In particular, thecombination as described herein may be administered. In the method ofthe present invention, the patient may be the patient defined herein.

Yet another aspect of the present invention refers to the use of thecombination as described herein for the manufacture of a medicament forthe treatment of a medical indication, as described herein. For example,the combination of the present invention can be used for the manufactureof a medicament for the treatment of diabetes type 2 patients, or/andfor the treatment of conditions associated with diabetes type 2. Inparticular, the combination of the present invention can be used for themanufacture of a medicament for the improvement of glycemic control,improvement of glucose tolerance, improvement of postprandial plasmaglucose concentration, improvement of fasting plasma glucoseconcentration, improvement of the HbA1c value or/and improvement offasting plasma insulin concentration. The patient may be a patient asdefined herein.

The invention is further illustrated by the following example andfigures.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1—Study design. End of treatment* indicates once the anticipatedEnd of Study date is known, the investigational site must contact thepatient to schedule the End of treatment visit (±4 weeks relative to theend date of the study) for end of treatment assessments and the patientcontinues the study medication until this visit.

FIG. 2—Kaplan-Meier plot of time to treatment discontinuation due to anyreason—Randomized population.

FIG. 3—Plot of mean change in HbA1c (%) from baseline by visit up toWeek 24—mITT population. LOCF=Last observation carried forward. Note:The plot includes measurements before the introduction of rescuemedication and up to 3 days after the last dose of the double-blindinvestigational product injection on or before Visit 12 (Week 24), orDay 169 if Visit 12 (Week 24) is not available.

FIG. 4—Plot of mean change in fasting plasma glucose (mmol/L) frombaseline by visit up to Week 24—mITT population. LOCF=Last observationcarried forward. Note: The plot includes measurements before theintroduction of rescue medication and up to 1 day after the last dose ofthe double-blind investigational product injection on or before Visit 12(Week 24), or Day 169 if Visit 12 (Week 24) is not available.

FIG. 5 Plot of mean change in body weight (kg) from baseline by visit upto Week 24—mITT population. LOCF=Last observation carried forward. Note:The plot includes measurements before the introduction of rescuemedication and up to 3 days after the last dose of the double-blindinvestigational product injection on or before Visit 12 (Week 24), orDay 169 if Visit 12 (Week 24) is not available.

FIG. 6—Plot of mean change in HbA1c (%) from baseline by visit-mITTpopulation. LOCF=Last observation carried forward, EOT=Last on-treatmentvalue. Note: The analysis excludes measurements obtained after theintroduction of rescue medication and/or after the treatment cessationplus 3 days. For Week 24 (LOCF), the analysis includes measurementsobtained up to 3 days after the last dose of the double-blindinvestigational product injection on or before Visit 12 (Week 24), orDay 169 if Visit 12 (Week 24) is not available.

FIG. 7—Plot of mean change in fasting plasma glucose (mmol/L) frombaseline by visit—mITT population. LOCF=Last observation carriedforward, EOT=Last on-treatment value. Note: The analysis excludesmeasurements obtained after the introduction of rescue medication and/orafter the treatment cessation plus 1 day. For Week 24 (LOCF), theanalysis includes measurements obtained up to 1 day after the last doseof the double-blind investigational product injection on or before Visit12 (Week 24), or Day 169 if Visit 12 (Week 24) is not available.

FIG. 8—Plot of mean change in body weight (kg) from baseline byvisit—mITT population. LOCF=Last observation carried forward, EOT=Laston-treatment value. Note: The analysis excludes measurements obtainedafter the introduction of rescue medication and/or after the treatmentcessation plus 3 days. For Week 24 (LOCF), the analysis includesmeasurements obtained up to 3 days after the last dose of thedouble-blind investigational product injection on or before Visit 12(Week 24), or Day 169 if Visit 12 (Week 24) is not available.

EXAMPLE Summary

The Example refers to a randomized, double-blind, placebo-controlled,2-arm, unbalanced design, parallel-group, multicenter, multinationalstudy assessing the efficacy and safety of lixisenatide on top ofpioglitazone in patients with type 2 diabetes, not adequately controlledwith pioglitazone. The approximate minimum double-blind study durationper patient was 79 weeks (up to 2 weeks screening+1 week run-in +24weeks main double-blind treatment+variable extension+3 days follow-up).

The study was conducted in 150 centers in 13 countries. The primaryobjective of the study was to assess the efficacy of lixisenatide onglycemic control in comparison to placebo as an add-on treatment topioglitazone in terms of HbA1c reduction (absolute change) over a periodof 24 weeks.

A total of 484 patients were randomized to one of two treatment groups(323 in lixisenatide and 161 in placebo). All randomized patients wereexposed to the study treatment. Demographics and baselinecharacteristics were generally similar across the treatment groups. Fivepatients (3 on lixisenatide and 2 on placebo) were excluded from themodified intent-to-treat (mITT) population for efficacy analyses due tono post-baseline efficacy data. During the overall study treatmentperiod, 136 (28.1%) patients prematurely discontinued the studytreatment (26.0% for lixisenatide and 32.3% for placebo). For thelixisenatide group, the main reason for treatment discontinuation was“other reasons” (10.5% versus 12.4% for placebo) followed by “adverseevents” (9.0% versus 8.7% for placebo).

Efficacy analyses are based on the main 24-week double-blind treatmentperiod. The least squares (LS) mean changes from baseline to Week 24 inHbA1c were −0.90% in the lixisenatide group and −0.34% in the placebogroup (LS mean difference vs. placebo=−0.56%; p-value <0.0001). Thepercentages of patients reaching HbA1c≤6.5% or <7% at Week 24 weresignificantly higher in the lixisenatide group than in the placebo group(for HbA1c≤6.5%, 28.9% in the lixisenatide group versus 10.1% in theplacebo group; for HbA1c<7%, 52.3% in the lixisenatide group versus26.4% in the placebo group). The HbA1c responder analysis (HbA1c≤6.5% or<7% at Week 24) using Cochran-Mantel-Haenszel (CMH) method also showed asignificant treatment difference between lixisenatide and placebo atWeek 24 (p-value <0.0001).

For fasting plasma glucose (FPG), a significant decrease from baselineto Week 24 was observed in the lixisenatide group compared to theplacebo group (LS mean difference versus placebo=−0.84 mmol/L; p-value<0.0001). For body weight, the LS mean decrease was 0.21 kg frombaseline at Week 24 in the lixisenatide group, compared to a LS meanincrease of 0.21 kg in the placebo group, and the difference between the2 groups was not significant (LS mean difference versus placebo=−0.41kg). Per the testing strategy for multiplicity adjustment, theinferential testing for the subsequent efficacy variables wasexploratory, since the body weight analysis failed to show astatistically significant difference. There is no relevant differenceobserved in β-cell function assessed by HOMA-β between lixisenatide andplacebo with LS mean difference of −0.25 (95% Cl: [−6.579 to 6.070]).The percentage of patients requiring rescue therapy at Week 24 wassubstantially lower in the lixisenatide group (12 patients [3.8%]),compared to the placebo group (18 [11.3%]). For fasting plasma insulin(FPI), the LS mean reduction was greater in the lixisenatide group thanin the placebo group with LS mean difference of −9.36 pmol/L (95% Cl:[−16.586 to −2.124]).

Safety analyses are based on the treatment period of the whole study.Lixisenatide was well tolerated. The proportions of patients whoexperienced treatment emergent adverse events (TEAEs) were 87.9% in thelixisenatide group and 83.2% in the placebo group. No patients in thelixisenatide group died, but 2 patients in the placebo group died. Onehad a treatment emergent acute myocardial infarction leading to deathand the other died due to a post-treatment AE (end stage debility)following respiratory failure with multiorgan failure. The percentage ofpatients who had serious TEAEs was lower in the lixisenatide group(7.4%) than in the placebo group (9.3%). The most commonly reportedTEAEs in the lixisenatide group were nausea (26% versus 13.7% forplacebo), followed by nasopharyngitis (16.4% versus 14.9% for placebo)and headache (13.3% versus 11.8% for placebo). During the on-treatmentperiod of the whole study, 23 (7.1%) patients in the lixisenatide grouphad symptomatic hypoglycemia per protocol definition, compared to 7(4.3%) in the placebo group. None of the symptomatic hypoglycemia eventswere severe in intensity. Twenty-two (6.8%) patients in the lixisenatidegroup and 8 (5.0%) in the placebo group experienced injection sitereaction AEs. A total of 12 patients (9 [2.8%] patients in thelixisenatide group and 3 [1.9%] in the placebo group) reported 19 eventsthat were adjudicated as allergic reactions by the Allergic ReactionAssessment Committee (ARAC). Of these, 5 events in 3 patients in thelixisenatide group (1 patient with allergic dermatitis, 1 withurticaria, and 1 with angioedema, anaphylactic reaction, and allergicconjunctivitis) were adjudicated as possibly related to IP. No eventswere adjudicated as possibly related to IP in the placebo group. No caseof pancreatitis or thyroid cancer was reported in the study.

1 OBJECTIVES 1.1 Primary Objective

The primary objective of this study was to assess the efficacy oflixisenatide on glycemic control in comparison to placebo as an add-ontreatment to pioglitazone in type 2 diabetes patients treated withpioglitazone in terms of absolute HbA1c reduction over a period of 24weeks.

1.2 Key Secondary Objective(S)

The secondary objectives of this study were:

-   -   To assess the effects of lixisenatide on        -   Percentage of patients reaching HbA1c<7%,        -   Percentage of patients reaching HbA1c≤6.5%,        -   Fasting Plasma Glucose (FPG),        -   Body weight,        -   β-cell function assessed by HOMA-β,        -   Fasting plasma insulin (FPI).    -   To assess lixisenatide safety and tolerability.

2 TRIAL DESIGN

This was an unbalanced (2:1), randomized, double-blind,placebo-controlled, 2-arm parallel-group, multicenter, multinationalstudy with an variable extension period comparing lixisenatide treatmentwith placebo in type 2 diabetes patients (300 patients in lixisenatidearm and 150 patients in placebo arm). The study was double-blind withregard to active and placebo treatments. The study drug volume (i.e.dose of active drug or matching placebo) was not blinded. The patientswere stratified by screening values of HbA1c (<8%, ≥8%) and metforminuse (Yes, No) at screening.

The approximate minimum double-blind study duration per patient was 79weeks (up to 2 weeks screening+1 week run-in +24 weeks main double-blindtreatment+variable extension+3 days follow-up). Patients who hadcompleted the 24-week main double-blind period underwent a variabledouble blind extension period, which ended for all patientsapproximately at the scheduled date of week 76 visit (V25) for the lastrandomized patient.

The trial design is illustrated by FIG. 1.

3 PRIMARY AND KEY SECONDARY ENDPOINTS 3.1 Primary Endpoint

The primary efficacy variable was the absolute change in HbA1c frombaseline to Week 24, which was defined as: HbA1c value at Week 24—HbA1cvalue at baseline.

If a patient permanently discontinued the treatment or received rescuetherapy during the main 24-week double-blind treatment period or did nothave HbA1c value at Week 24, the last post-baseline HbA1c measurementduring the main 24-week double-blind on-treatment period was used asHbA1c value at Week 24 (last observation carried forward [LOCF]procedure).

3.2 Key Secondary Endpoints 3.2.1 Key Secondary Efficacy Endpoints

For secondary efficacy variables, the same procedure for handlingmissing assessments/early discontinuation was applied as for the primaryefficacy variable.

Continuous Variables:

-   -   Change in FPG (mmol/L) from baseline to Week 24,    -   Change in body weight (kg) from baseline to Week 24,    -   Change in β-cell function assessed by HOMA-β from baseline to        Week 24,    -   Change in FPI (pmol/L) from baseline to Week 24.

Categorical Variables:

-   -   Percentage of patients with HbA1c<7% at Week 24,    -   Percentage of patients with HbA1c≤6.5% at Week 24,    -   Percentage of patients requiring rescue therapy during the main        24-week double-blind treatment period,    -   Percentage of patients with ≥5% weight loss (kg) from baseline        at Week 24.

3.2.2 Safety Endpoints

The safety analysis was based on the reported TEAEs and other safetyinformation including symptomatic hypoglycemia and severe symptomatichypoglycemia, local tolerability at injection site, allergic events (asadjudicated by ARAC), suspected pancreatitis, increased calcitonin,vital signs, 12-lead ECG and laboratory tests.

Major cardiovascular events were also collected and adjudicated in ablinded manner by a Cardiovascular events Adjudication Committee (CAC).The adjudicated and confirmed events by CAC from this study and otherlixisenatide phase 3 studies will be pooled for analyses and summarizedin a separate report based on the statistical analysis plan for theoverall cardiovascular assessment of lixisenatide. The KRM/CSR will notpresent the summary of the adjudicated and confirmed CV events from thisstudy.

4 SAMPLE SIZE CALCULATION ASSUMPTIONS

The sample size/power calculations were performed based on the primaryvariable, absolute change from baseline to Week 24 in HbA1c.

Three-hundred (300) patients in the lixisenatide treatment and 150 inthe placebo treatment arm provided a power of 96% (or 86%) to detectdifferences of 0.5% (or 0.4%) in the absolute change from baseline toWeek 24 in HbA1c between the lixisenatide group and the placebo group.This calculation assumed a common standard deviation of 1.3% with a2-sided test at the 5% significance level. The sample size calculationswere based upon the 2-sample t-test and made using nQuery Advisor® 5.0.Standard deviation was estimated in a conservative manner frompreviously conducted diabetes studies (based on published data ofsimilarly designed study and on internal data, not published), takinginto account early dropout.

5 STATISTICAL METHODS 5.1 Analysis Populations

The modified intent-to-treat (mITT) population consisted of allrandomized patients who received at least 1 dose of double-blindinvestigational product (IP), and had both a baseline assessment and atleast 1 post-baseline assessment of efficacy variables.

The safety population was defined as all randomized patients who took atleast one dose of the double-blind IP.

5.2 Primary Efficacy Analysis

The primary efficacy variable (change in HbA1c from baseline to Week 24)was analyzed using an analysis of covariance (ANCOVA) model withtreatment groups (lixisenatide and placebo), randomization strata ofscreening HbA1c (<8.0, 8.0%), randomization strata of metformin use(Yes, No) at screening, and country as fixed effects and the baselineHbA1c value as a covariate.

Both means and adjusted means for lixisenatide and placebo wereprovided, as well as 95% confidence intervals (CI) constructed foradjusted mean differences between lixisenatide and placebo. Differencebetween lixisenatide and placebo and two-sided 95% confidence interval,as wells as p-value were estimated within the framework of ANCOVA.

The primary analysis of the primary efficacy variable was performedbased on the mITT population and the measurements obtained during themain 24-week double-blind on-treatment period for efficacy variables.The main 24-week double-blind on-treatment period for efficacy analysiswas the time from the first dose of the double-blind IP up to 3 days(except for FPG and FPI, which was up to 1 day) after the last dose ofthe double-blind IP injection on or before V12/Week 24 visit (or D169 ifV12/Week 24 visit is missing), or up to the introduction of the rescuetherapy, whichever the earliest. The LOCF procedure was used by takingthis last available post-baseline on-treatment HbA1c measurement (beforethe introduction of rescue therapy) as the HbA1c value at Week 24.

5.3 Key Secondary Efficacy Analysis

A step down testing procedure was applied in order to ensure the controlof type 1 error. Once the primary variable was statistically significantat α=0.05, the testing procedure was performed to test the followingsecondary efficacy variables by the following prioritized order. Thetests stop as soon as an endpoint was found not statisticallysignificant at α=0.05.

-   -   Change in FPG (mmol/L) from baseline to Week 24,    -   Change in body weight (kg) from baseline to Week 24,    -   Change in β-cell function assessed by HOMA-β from baseline to        Week 24,    -   Percentage of patients requiring rescue therapy during the        24-week treatment period,    -   Change in FPI (mmol/L) from baseline to Week 24.

All continuous secondary efficacy variables at Week 24 as described inSection 3.2.1 were analyzed using the similar approach and ANCOVA modelas described in Section 5.2 for the primary analysis of the primaryefficacy endpoint. The adjusted estimates of the treatment meandifference between lixisenatide and placebo and two-sided 95% confidenceintervals were provided.

The following categorical secondary efficacy variables at Week 24 wereanalyzed using a Cochran-Mantel-Haenszel (CMH) method stratified onrandomization strata (screening HbA1c [<8.0, ≥8.0%] and screeningmetformin use [Yes, No]):

-   -   Percentage of patients with HbA1c<7.0% at Week 24,    -   Percentage of patients with HbA1c≤6.5% at Week 24,    -   Percentage of patients requiring rescue therapy during the main        24-week double-blind treatment period.

Number and percentage of patients with 5% weight loss from baseline atWeek 24 were presented by treatment groups.

Results for all efficacy endpoints during the variable extension periodand at the end of treatment were to be evaluated by descriptivestatistics only.

5.4 Safety Analysis

The safety analyses were primarily based on the on-treatment period ofthe whole study. The on-treatment period of the whole study was definedas the time from the first dose of double-blind IP up to 3 days afterthe last dose of IP administration during the whole study periodregardless of rescue status. The 3-day interval was chosen based on thehalf-life of the IP (approximately 5 times the half-life).

In addition, the safety analyses for the 24-week double-blind treatmentperiod will be summarized in the CSR.

The summary of safety results (descriptive statistics or frequencytables) is presented by treatment groups.

6 RESULTS 6.1 Study Patients 6.1.1 Patient Accountability

The study was conducted in 150 centers in 13 countries (Austria, Canada,France, Germany, Greece, Guatemala, India, Mexico, Peru, Puerto Rico,Romania, Turkey, and United States of America). A total of 906 patientswere screened and 484 were randomized to 1 of the 2 treatment groups.The most common reason for non-randomization was HbA1c value out ofrange at the screening visit as defined per protocol (283 [31.2%] out of906 screened patients).

All 484 randomized patients were exposed to the study treatment and 5patients (3 in the lixisenatide group and 2 in the placebo group) wereexcluded from mITT population for efficacy analyses due to nopost-baseline efficacy data. Table 1 provides the number of patientsincluded in each analysis population.

Due to his investigator's non-compliance to the clinical protocol andviolation of good clinical practices, one patient in the lixisenatidegroup was discontinued by the sponsor. The patient was exposed for 113days and included in the analyses for safety and efficacy.

TABLE 1 Analysis populations-Randomized population Placebo LixisenatideAll (N = 161) (N = 323) (N = 484) Randomized population 161 (100%)  323(100%)  484 (100%)  Efficacy population 159 (98.8%) 320 (99.1%) 479(99.0%) Modified Intent-to-Treat (mITT) Safety population 161 323 484Note: The safety patients are tabulated according to treatment actuallyreceived (as treated). For the efficacy population, patients aretabulated according to their randomized treatment (as randomized).

6.1.2 Study Disposition

Table 2 provides the summary of patient disposition for each treatmentgroup. During the overall treatment period, 136 (28.1%) patientsprematurely discontinued the study treatment (26.0% for lixisenatide and32.3% for placebo). In the lixisenatide group, the main reason fortreatment discontinuation was “other reasons” (10.5% versus 12.4% forplacebo) followed by “adverse events” (9.0% versus 8.7% for placebo).

Similar results were observed for the 24-week treatment period, where atotal of 59 (12.2%) patients prematurely discontinued the studytreatment (10.8% for lixisenatide and 14.9% for placebo) with mainreasons in the lixisenatide group also being “other reasons” (4.0%versus 5.0% for placebo) and “adverse events” (4.0% versus 5.6% forplacebo). The category of “other reasons” were confirmed byinvestigators to be not AE related, and included but was not limited topersonal reasons, schedule conflict, moving, injection not convenient,site closure etc. The time-to-onset of treatment discontinuation due toany reason for the overall treatment period is depicted in FIG. 2. Alower rate of discontinuation was observed in the lixisenatide groupduring the whole treatment period, as compared to the placebo group. Theincrease of the rate of discontinuation from around 25 to 100% in thelixisenatide group at the end of the study was due to the patient whohad been followed the longest, discontinued at Day 874.

One patient in the lixisenatide group who discontinued treatment due to“Glycosylated haemoglobin increased” in Table 20 was counted as lack ofefficacy in Table 2, while 2 patients in the placebo group whodiscontinued for AE were not counted in Table 20 because their AEsleading to treatment discontinuation occurred during the pre- orpost-treatment period.

TABLE 2 Patient disposition-Randomized population Placebo Lixisenatide(N = 161) (N = 323) Randomized and treated 161 (100%) 323 (100%) Did notcomplete 24-week double-blind study treatment 24 (14.9%) 35 (10.8%)Subjects request for 24-week treatment discontinuation 20 (12.4%) 26(8.0%) Reason for 24-week study treatment discontinuation 24 (14.9%) 35(10.8%) Adverse event 9 (5.6%) 13 (4.0%) Lack of efficacy 5 (3.1%) 2(0.6%) Poor compliance to protocol 1 (0.6%) 4 (1.2%) Lost to follow-up 1(0.6%) 3 (0.9%) Other reasons 8 (5.0%) 13 (4.0%) Did not completedouble-blind study treatment 52 (32.3%) 84 (26.0%) Subjects request fortreatment discontinuation 42 (26.1%) 65 (20.1%) Reason for studytreatment discontinuation 52 (32.3%) 84 (26.0%) Adverse event 14 (8.7%)29 (9.0%) Lack of efficacy 10 (6.2%) 11 (3.4%) Poor compliance toprotocol 6 (3.7%) 6 (1.9%) Lost to follow-up 2 (1.2%) 4 (1.2%) Otherreasons 20 (12.4%) 34 (10.5%) Status at last study contact 161 (100%)323 (100%) Alive 155 (96.3%) 318 (98.5%) Dead 2 (1.2%) 0 Lost tofollow-up 4 (2.5%) 5 (1.5%) Note: Percentages are calculated using thenumber of randomized patients as denominator.

6.1.3 Demographics and Baseline Characteristics

The demographic and patient baseline characteristics were generallysimilar across treatment groups for the safety population (Table 3). Themedian age was 56 years and 52.5% were male. The study population wasprimarily Caucasian (83.7%) and 67.6% of the safety population had a BMI30 kg/m².

Disease characteristics including diabetic history were generallycomparable between two treatment groups (Table 4). The median durationof diabetes was 7.22 years and the median age at onset of diabetes was48 years. Patients were on pioglitazone for a median duration of 0.83years and the median daily dose was 30 mg. At screening, 81% of patientshad used metformin with a median duration of 3.37 years and a mediandaily dose of 2000 mg.

HbA1c, FPG and HOMA-13 at baseline were generally comparable acrosstreatment groups for the safety population (Table 5). A higher mean bodyweight at baseline was observed in the placebo group (96.74 kg) comparedto the lixisenatide group (92.93 kg). Both the mean and the median ofFPI are higher in the placebo group (66.07 pmol/L and 53.78 pmol/L,respectively) compared to the lixisenatide group (63.32 pmol/L and 46.14pmol/L, respectively). The average HbA1c at baseline was 8.07%.

TABLE 3 Demographics and patient characteristics at screening orbaseline-Safety population Placebo Lixisenatide All (N = 161) (N = 323)(N = 484) Age (years) Number 161 323 484 Mean(SD) 55.3 (9.5) 56.0 (9.5)55.8 (9.5) Median 55.0 56.0 56.0 Min:Max 28:77 26:82 26:82 Age group(years) [n (%)] Number 161 323 484 <50 41 (25.5%) 66 (20.4%) 107(22.1%) >=50 to <65 90 (55.9%) 199 (61.6%) 289 (59.7%) >=65 to <75 29(18.0%) 49 (15.2%) 78 (16.1%) >=75   1 (0.6%) 9 (2.8%) 10 (2.1%) Gender[n (%)] Number 161 323 484 Male 82 (50.9%) 172 (53.3%) 254 (52.5%)Female 79 (49.1%) 151 (46.7%) 230 (47.5%) Race [n (%)] Number 161 323484 Caucasian/White 132 (82.0%) 273 (84.5%) 405 (83.7%) Black 9 (5.6%)14 (4.3%) 23 (4.8%) Asian/Oriental 8 (5.0%) 14 (4.3%) 22 (4.5%) Other 12(7.5%) 22 (6.8%) 34 (7.0%) Ethnicity [n (%)] Number 161 323 484 Hispanic41 (25.5%) 87 (26.9%) 128 (26.4%) Not Hispanic 120 (74.5%) 236 (73.1%)356 (73.6%) Screening HbA1c (%) Number 161 322 483 Mean(SD) 8.15 (0.82)8.15 (0.82) 8.15 (0.82) Median 8.00 8.00 8.00 Min:Max  7.0:10.0 7.0:10.0  7.0:10.0 Randomization strata of screening HbA1c (%) [n (%)]Number 161 323 484  <8 79 (49.1%) 159 (49.2%) 238 (49.2%)  ≥8 82 (50.9%)164 (50.8%) 246 (50.8%) Randomization strata of metformin use atscreening [n (%)] Number 161 323 484 Yes 132 (82.0%) 264 (81.7%) 396(81.8%) No 29 (18.0%) 59 (18.3%) 88 (18.2%) Baseline BMI (kg/m)² Number161 323 484 Mean(SD) 34.44 (7.04) 33.66 (6.71) 33.92 (6.82) Median 33.6933.59 33.62 Min:Max 21.7:52.8 20.2:62.7 20.2:62.7 Baseline BMI Group(kg/m)² [n (%)] Number 161 323 484 <30 51 (31.7%) 106 (32.8%) 157(32.4%) ≥30 110 (68.3%) 217 (67.2%) 327 (67.6%) BMI = Body Mass Index.

TABLE 4 Disease characteristics at screening or baseline-Safetypopulation Placebo Lixisenatide All (N = 161) (N = 323) (N = 484)Duration of diabetes (years) Number 161 323 484 Mean (SD) 8.09 (5.58)8.11 (5.44) 8.10 (5.48) Median 7.27 7.18 7.22 Min:Max  1.0:30.4 0.9:32.1  0.9:32.1 Age at onset of type 2 diabetes (years) Number 161323 484 Mean (SD) 47.22 (9.41)  47.84 (8.88)  47.63 (9.05)  Median 48.0048.00 48.00 Min:Max 21.0:69.0 20.0:74.0 20.0:74.0 Duration ofpioglitazone treatment (years) Number 161 323 484 Mean (SD) 1.79 (2.51)1.69 (2.00) 1.72 (2.18) Median 0.77 0.87 0.83 Min:Max  0.2:18.3 0.2:11.2  0.2:18.3 Daily dose of pioglitazone (mg) at baseline Number161 323 484 Mean (SD) 33.26 (6.21)  33.81 (6.64)  33.63 (6.50)  Median30.00 30.00 30.00 Min:Max 30.0:45.0 30.0:60.0 30.0:60.0 Categorizeddaily dose of pioglitazone at baseline (mg) [n(%)] Number 161 323 484<30 0 0 0 ≥30-<45 126 (78.3%) 242 (74.9%) 368 (76.0%) ≥45  35 (21.7%) 81 (25.1%) 116 (24.0%) Metformin use at screening [n (%)] Number 161323 484 Yes 131 (81.4%) 261 (80.8%) 392 (81.0%) No  30 (18.6%)  62(19.2%)  92 (19.0%) Duration of metformin treatment (years) Number 131261 392 Mean(SD) 4.27 (3.84) 4.34 (3.77) 4.32 (3.79) Median 3.33 3.373.37 Min:Max  0.3:20.5  0.2:25.8  0.2:25.8 Daily dose of metformin atbaseline (mg) Number 131 261 392 Mean(SD) 1872.90 (273.25)  1895.02(295.24)  1887.63 (287.92)  Median 1700.00 2000.00 2000.00 Min:Max1500.0:2550.0 1500.0:3000.0 1500.0:3000.0 Categorized daily dose ofmetformin at baseline (mg) [n (%)] Number 131 261 392 <1500  0 0 0  1500-<2500 119 (90.8%) 236 (90.4%) 355 (90.6%)   2500-<3000 12 (9.2%)23 (8.8%) 35 (8.9%) ≥3000  0  2 (0.8%)  2 (0.5%) History of gestationaldiabetes [n (%)] Number (Female) 79 151 230 Yes (Female)  6 (7.6%) 15(9.9%) 21 (9.1%) No (Female)  73 (92.4%) 136 (90.1%) 209 (90.9%) Prioruse of GLP-1 receptor agonist [n (%)] Number 161 323 484 Yes  5 (3.1%)17 (5.3%) 22 (4.5%) No 156 (96.9%) 306 (94.7%) 462 (95.5%) Diabeticretinopathy [n (%)] Number 160 323 483 Yes  5 (3.1%) 13 (4.0%) 18 (3.7%)No 151 (94.4%) 303 (93.8%) 454 (94.0%) Unknown  4 (2.5%)  7 (2.2%) 11(2.3%) Diabetic sensory or motor neuropathy [n (%)] Number 160 323 483Yes  19 (11.9%)  69 (21.4%)  88 (18.2%) No 140 (87.5%) 251 (77.7%) 391(81.0%) Unknown  1 (0.6%)  3 (0.9%)  4 (0.8%) Diabetic autonomicneuropathy [n (%)] Number 160 323 483 Yes  5 (3.1%)  3 (0.9%)  8 (1.7%)No 155 (96.9%) 316 (97.8%) 471 (97.5%) Unknown 0  4 (1.2%)  4 (0.8%)Diabetic nephropathy [n (%)] Number 160 323 483 Yes Microalbuminuria  8(5.0%) 14 (4.3%) 22 (4.6%) Overt proteinuria  5 (3.1%) 10 (3.1%) 15(3.1%) Impaired renal function 0  1 (0.3%)  1 (0.2%) Dialysis ortransplantation 0  1 (0.3%)  1 (0.2%) Unknown 0 0 0 No  3 (1.9%)  2(0.6%)  5 (1.0%) Unknown 148 (92.5%) 300 (92.9%) 448 (92.8%)  4 (2.5%) 9 (2.8%) 13 (2.7%) Categorized microalbumin at randomization [n (%)]Number 67 139 206 <3 mg/L (Not reportable)  9 (13.4%)  15 (10.8%)  24(11.7%) ≥3 mg/L (Reportable)  58 (86.6%) 124 (89.2%) 182 (88.3%)  <20mg/L  37 (55.2%)  84 (60.4%) 121 (58.7%) ≥20-<200 mg/L  18 (26.9%)  33(23.7%)  51 (24.8%) ≥200 mg/L  3 (4.5%)  7 (5.0%) 10 (4.9%) Creatinineclearance at screening (ml/min) Number 158 309 467 Mean (SD) 136.34(57.86)  128.08 (46.51)  130.88 (50.73)  Median 126.32 121.42 122.24Min:Max  46.7:438.3  38.3:349.5  38.3:438.3 Categorized creatinineclearance at screening [n (%)] Number 158 309 467 <30 ml/min (severerenal impairment) 0 0 0 ≥30-<50 ml/min (moderate renal impairment)  1(0.6%)  5 (1.6%)  6 (1.3%) ≥50-≤80 ml/min (mild renal impairment) 15(9.5%) 28 (9.1%) 43 (9.2%) >80 ml/min (no renal impairment) 142 (89.9%)276 (89.3%) 418 (89.5%) GLP-1 = Glucagon like peptide-1. Creatinineclearance value is derived using the equation of Cockcroft and Gault.

TABLE 5 Baseline efficacy variables-Safety population PlaceboLixisenatide All (N = 161) (N = 323) (N = 484) HbA1c (%) Number 161 323484 Mean(SD) 8.06 (0.79) 8.08 (0.90) 8.07 (0.86) Median 7.90 7.90 7.90Min:Max 6.5:10.2 6.5:12.7 6.5:12.7 FPG (mmol/L) Number 161 323 484Mean(SD) 9.13 (2.20) 9.11 (2.15) 9.12 (2.16) Median 8.70 8.80 8.80Min:Max 4.7:17.9 4.5:17.2 4.5:17.9 Weight (kg) Number 161 323 484Mean(SD) 96.74 (25.58) 92.93 (22.90) 94.20 (23.87) Median 92.90 92.0092.20 Min:Max 45.0:198.3 48.5:162.7 45.0:198.3 FPI (pmol/L) Number 142300 442 Mean (SD) 66.07 (48.12) 63.32 (57.69) 64.21 (54.76) Median 53.7846.14 48.72 Min:Max  4.9:356.1  9.4:635.7  4.9:635.7 HOMA-β Number 141300 441 Mean (SD) 36.23 (26.50) 34.69 (30.30) 35.18 (29.12) Median 29.2926.52 27.49 Min:Max  1.1:157.6  3.8:276.3  1.1:276.3 FPG = FastingPlasma Glucose; FPI = Fasting Plasma Insulin.

6.1.4 Dosage and Duration

The average treatment exposure was 560.2 days (80 weeks) in thelixisenatide group, compared to 518.6 days (74 weeks) in the placebogroup (Table 6). Of 323 lixisenatide treated patients, 286 (88.5%) wereexposed to IP for 24 weeks (169 days) or longer, and 199 (61.6%) wereexposed for 18 months (547 days) or longer. Five patients did not recordthe last administration date on CRF page “End of treatment” and hencetheir duration of exposure was set to missing following the SAP datahandling convention.

At the end of double-blind treatment, 92.3% of patients reached thetarget daily dose of 20 μg in the lixisenatide group, lower than theplacebo group (97.5%) (Table 7). Similar result was observed at the endof 24-week double-blind treatment period (92.6% for lixisenatide versus98.8% for placebo) (Table 8). The dose at the end of titration ispresented in Table 28.

TABLE 6 Exposure to investigational product-Safety population PlaceboLixisenatide (N = 161) (N = 323) Cumulative duration of treatment 225.8490.8 exposure (patient years) Duration of study treatment (days) Number159 320 Mean (SD) 518.6 (232.5) 560.2 (226.2) Median 588.0 615.5 Min:Max3:925 6:874 Duration of study treatment by category [n (%)] Missingduration 2 (1.2%) 3 (0.9%)  1-14 days 1 (0.6%) 7 (2.2%) 15-28 days 1(0.6%) 6 (1.9%) 29-56 days 5 (3.1%) 8 (2.5%) 57-84 days 7 (4.3%) 3(0.9%)  85-168 days 9 (5.6%) 10 (3.1%) 169-364 days 16 (9.9%) 25 (7.7%)365-546 days 23 (14.3%) 62 (19.2%) 547-728 days 76 (47.2%) 126(39.0%) >728 days 21 (13.0%) 73 (22.6%) Cumulative duration of studytreatment by category [n (%)] Missing duration 2 (1.2%) 3 (0.9%) ≥1 day159 (98.8%) 320 (99.1%)  ≥15 days 158 (98.1%) 313 (96.9%)  ≥29 days 157(97.5%) 307 (95.0%)  ≥57 days 152 (94.4%) 299 (92.6%)  ≥85 days 145(90.1%) 296 (91.6%) ≥169 days 136 (84.5%) 286 (88.5%) ≥365 days 120(74.5%) 261 (80.8%) ≥547 days 97 (60.2%) 199 (61.6%) ≥729 days 21(13.0%) 73 (22.6%) Duration of exposure = (date of the last double-blindinvestigational product injection − date of the first double-blindinvestigational product injection) + 1.

TABLE 7 Number (%) of patients by final total daily dose at the end ofthe double-blind treatment-Safety population Placebo Lixisenatide Finaldose (N = 161) (N = 323) <10 μg   1 (0.6%) 0 10 μg 2 (1.2%) 10 (3.1%) 15μg 1 (0.6%) 15 (4.6%) 20 μg 157 (97.5%) 298 (92.3%) Dose = Dose ofactive drug or volume-matched placebo. Note: Percentages are calculatedusing the number of safety patients as the denominator.

TABLE 8 Number(%) of patients by final total daily dose at the end of24-week treatment-Safety population Dose at the end of the 24- PlaceboLixisenatide week (N = 161) (N = 323) 10 μg  1 (0.6%) 10 (3.1%) 15 μg  1(0.6%) 14 (4.3%) 20 μg 159 (98.8%) 299 (92.6%) Dose = Dose of activedrug or volume-matched placebo. Note: Percentages are calculated usingthe number of safety patients as the denominator.

6.2 Efficacy 6.2.1 Primary Efficacy Endpoint Main Analysis

Table 9 summarizes the results of the primary efficacy parameter, changefrom baseline to Week 24 (LOCF) in HbA1c using an ANCOVA analysis.

The pre-specified primary analysis showed that treatment withlixisenatide resulted in a statistically significant decrease in HbA1cfrom baseline to Week 24, compared with the placebo group (LSmean-difference versus the placebo group=−0.56%; p-value <0.0001).

TABLE 9 Mean change in HbA1c (%) from baseline to Week 24-mITTpopulation Placebo Lixisenatide HbA1c (%) (N = 159) (N = 320) BaselineNumber 148 308 Mean (SD) 8.05 (0.78) 8.08 (0.91) Median 7.90 7.90Min:Max 6.5:10.2 6.5:12.7 Week 24 (LOCF) Number 148 308 Mean (SD) 7.59(0.96) 7.06 (0.96) Median 7.40 6.90 Min:Max 5.5; 10.4 5.3:11.3 Changefrom baseline to week 24 (LOCF) Number 148 308 Mean(SD) −0.46 (1.00)−1.02 (1.09) Median −0.40 −0.90 Min:Max −4.0:2.5 −5.4:3.5 LS Mean (SE)^(a)  −0.34 (0.100)  −0.90 (0.089) LS Mean difference (SE) vs. Placebo^(a)  −0.56 (0.088) 95% CI (−0.731 to −0.386) p-value <.0001 LOCF = Lastobservation carried forward. ^(a) Analysis of covariance (ANCOVA) modelwith treatment groups (lixisenatide and placebo), randomization strataof screening HbAlc (<8.0, ≥8.0%), randomization strata of metformin useat screening, and country as fixed effects and baseline HbAlc value as acovariate. Note: The analysis includes measurements before theintroduction of rescue medication and up to 3 days after the last doseof the double-blind investigational product injection on or before Visit12 (Week 24), or Day 169 if Visit 12 (Week 24) is not available.Patients with both baseline and Week 24 (LOCF) measurements areincluded.

FIG. 3 illustrates the mean (±SE) change from baseline in HbA1c overtime during the main 24-week double-blind treatment period. FIG. 6 inthe appendix displays the mean (±SE) change from baseline in HbA1c overtime up to Week 76. The reduction of HbA1c was maintained over timebeyond 24 weeks.

Secondary Analysis

Table 10 summarizes the proportion of patients with treatment responseHbA1c<6.5% or <7% at Week 24, respectively. The analysis of HbA1cresponders using the CMH method showed a statistically significanttreatment difference between the lixisenatide group and the placebogroup (p-value <0.0001).

TABLE 10 Number (%) of patients with HbA1c value 6.5% or <7%respectively at Week 24-mITT population Placebo Lixisenatide HbA1c (%)(N = 159) (N = 320) Number 148 308 ≤6.5%  15 (10.1%)  89 (28.9%) >6.5%133 (89.9%) 219 (71.1%) p-value vs. placebo^(a) <0.0001 Number 148 308<7.0%  39 (26.4%) 161 (52.3%) ≥7.0% 109 (73.6%) 147 (47.7%) p-value vs.placebo^(a) <0.0001 ^(a)Cochran-Mantel-Haenszel (CMH) method stratifiedby randomization strata of screening HbA1c (<8.0 or ≥8.0%) andrandomization strata of metformin use at screening (Yes or No). Note:The analysis includes measurements before the introduction of rescuemedication and up to 3 days after the last dose of the double-blindinvestigational product injection on or before Visit 12 (Week 24), orDay 169 if Visit 12 (Week 24) is not available.

6.2.2 Key Secondary Efficacy Endpoints

The ANCOVA analyses of FPG, body weight, HOMA-β and FPI are presented inthis section. FIG. 4 and FIG. 5 illustrate the mean (±SE) change frombaseline in FPG and body weight over time during the main 24-weekdouble-blind treatment period. Mean (±SE) changes from baseline in FPGand body weight over time up to Week 76 are depicted in FIG. 7 and FIG.8 in the appendix respectively. The percentage of patients who wererescued during the main 24 week double-blind treatment period ispresented in Table 15.

For FPG, a significant decrease from baseline to Week 24 was observed inthe lixisenatide group compared to the placebo group (LS mean differenceversus placebo=−0.84 mmol/L; p-value <0.0001) (Table 11).

For body weight, the LS mean decrease was 0.21 kg from baseline at Week24 in the lixisenatide group, compared to a LS mean increase of 0.21 kgin the placebo group, but the difference between the 2 groups was notsignificant (LS mean difference versus placebo=−0.41 kg) (Table 12).About 9.2% patients in the lixisenatide group and 5.1% in the placebogroup had 5% weight loss from baseline to Week 24 (Table 13).

Per the testing strategy for multiplicity adjustment, the inferentialtesting for the subsequent efficacy variables was exploratory, since thebody weight analysis failed to show a statistically significantdifference.

For β-cell function assessed by HOMA-β, no relevant difference wasobserved between lixisenatide and placebo with LS mean difference of−0.25 (95% Cl: [−6.579 to 6.070]) (Table 14).

The percentage of patients requiring rescue therapy at Week 24 wassubstantially lower in the lixisenatide group (12 patients [3.8%])compared to the placebo group (18 patients [11.3%]) (Table 15).

For FPI, the LS mean reduction was greater in the lixisenatide groupthan in the placebo group with LS mean difference of −9.36 pmol/L (95%Cl: [−16.586 to −2.124]) (Table 16).

TABLE 11 Mean change in fasting plasma glucose (mmol/L) from baseline toWeek 24-mITT population Placebo Lixisenatide Fasting plasma glucose(mmol/L) (N = 159) (N = 320) Baseline Number 159 317 Mean(SD)   9.12(2.19)   9.14 (2.15) Median 8.70 8.80 Min:Max 4.7:17.9 4.5:17.2 Week 24(LOCF) Number 159 317 Mean(SD)   8.82 (2.32)   8.00 (2.29) Median 8.507.70 Min:Max 3.8:16.9 4.5:27.6 Change from baseline to week 24 (LOCF)Number 159 317 Mean(SD) −0.30 (2.12) −1.14 (2.24) Median −0.40 −1.10Min:Max −7.0:6.0    −9.6:17.6   LS Mean (SE) _(a)  −0.32 (0.215)  −1.16(0.192) LS Mean difference (SE) vs. Placebo _(a)  −0.84 (0.189) 95% CI(−1.209 to −0.467) p-value <.0001 LOCF = Last observation carriedforward. _(a) Analysis of covariance (ANCOVA) model with treatmentgroups (lixisenatide and placebo), randomization strata of screeningHbA1c (<8.0, ≥8.0%), metformin use at screening (Yes, No), and countryas fixed effects and baseline fasting plasma glucose as a covariate.Note: The analysis includes measurements before the introduction ofrescue medication and up to 1 day after the last dose of thedouble-blind investigational product injection on or before Visit 12(Week 24), or Day 169 if Visit 12 (Week 24) is not available. Patientswith both baseline and Week 24 (LOCF) measurements are included.

TABLE 12 Mean change in body weight (kg) from baseline to Week 24-mITTpopulation Placebo Lixisenatide Body weight (kg) (N = 159) (N = 320)Baseline Number 157 315 Mean (SD) 97.03 (25.81) 92.83 (23.01) Median93.00 92.00 Min:Max  45.0:198.3  48.5:162.7 Week 24 (LOCF) Number 157315 Mean(SD) 97.14 (26.19) 92.38 (23.17) Median 94.00 92.00 Min:Max 45.1:199.6  46.5:167.1 Change from baseline to week 24 (LOCF) Number157 315 Mean (SD) 0.12 (3.24) −0.44 (3.17)   Median 0.00 −0.50 Min:Max−11.9:11.7   −12.6:9.8    LS Mean (SE)^(a)  0.21 (0.357)  −0.21(0.324)   LS Mean difference (SE) vs. Placebo^(a)  −0.41 (0.314)   95%CI (−1.031 to 0.201) p-value 0.1864 LOCF = Last observation carriedforward. ^(a)Analysis of covariance (ANCOVA) model with treatment groups(lixisenatide and placebo), randomization strata of screening HbA1c(<8.0, ≥8.0%), metformin use at screening (Yes, No), and country asfixed effects and baseline body weight as a covariate. Note: Theanalysis includes measurements before the introduction of rescuemedication and up to 3 days after the last dose of the double-blindinvestigational product injection on or before Visit 12 (Week 24), orDay 169 if Visit 12 (Week 24) is not available. Patients with bothbaseline and Week 24 (LOCF) measurements are included.

TABLE 13 Number (%) of patients with 5% weight loss from baseline toWeek 24-mITT population Placebo Lixisenatide Weight loss (N = 159) (N =320) Number 157 315 ≥5%  8 (5.1%) 29 (9.2%) <5% 149 (94.9%) 286 (90.8%)The analysis includes measurements before the introduction of rescuemedication and up to 3 days after the last dose of the double-blindinvestigational product injection on or before Visit 12 (Week 24), orDay 169 if Visit 12 (Week 24) is not available.

TABLE 14 Mean change in HOMA-beta from baseline to Week 24-mITTpopulation Placebo Lixisenatide HomA-β (N = 159) (N = 320) BaselineNumber 124 281 Mean (SD) 37.37 (26.24) 33.93 (27.49) Median 30.03 26.27Min:Max 1.1:157.6    3.8:206.8 Week 24 (LOCF) Number 124 281 Mean(SD)44.26 (41.19) 42.48 (30.87) Median 34.23 33.21 Min:Max 2.0:356.7   3.6:208.9 Change from baseline to week 24 (LOCF) Number 124 281Mean(SD) 6.88 (36.07) 8.55 (27.98) Median 3.70 7.26 Min:Max−63.9:328.5    −140.1:163.1 LS Mean (SE)^(a) 6.98 (3.575)   6.72 (2.963)LS Mean difference (SE) vs. Placebo^(a) −0.25 (3.217) 95% CI (−6.579 to6.070) p-value 0.9369 LOCF = Last observation carried forward.^(a)Analysis of covariance (ANCOVA) model with treatment groups(lixisenatide and placebo), randomization strata of screening HbAlc(<8.0, ≥8.0%), metformin use at screening (Yes, No), and country asfixed effects and baseline HOMA-β value as a covariate. Note: Theanalysis includes measurements before the introduction of rescuemedication and up to 1 day after the last dose of the double-blindinvestigational product injection on or before Visit 12 (Week 24), orDay 169 if Visit 12 (Week 24) is not available. Patients with bothbaseline and Week 24 (LOCF) measurements are included.

TABLE 15 Number (%) of patients requiring rescue therapy during the main24-week double-blind treatment period-mITT population PlaceboLixisenatide Requiring rescue therapy (N = 159) (N = 320) Number 159 320Yes  18 (11.3%)  12 (3.8%) No 141 (88.7%) 308 (96.3%) p-value vs.placebo^(a)  0.0011 ^(a)Cochran-Mantel-Haenszel (CMH) method stratifiedby randomization strata of screening HbAlc (<8.0 or ≥8.0%) and metforminuse at screening (Yes, No).

TABLE 16 Mean change in fasting plasma insulin (pmol/L) from baseline toWeek 24-mITT population Placebo Lixisenatide Fasting plasma insulin(pmol/L) (N = 159) (N = 320) Baseline Number 125 281 Mean (SD)68.08 (49.25) 62.66 (56.88) Median 56.25 45.99 Min:Max 4.9:356.19.4:635.7 Week 24 (LOCF) Number 125 281 Mean (SD) 67.41 (47.06)57.11 (36.28) Median 56.68 48.14 Min:Max 9.5:274.9 7.7:358.8 Change frombaseline to Week 24 (LOCF) Number 125 281 Mean (SD) −0.67 (40.70)−5.55 (51.84) Median −1.65 0.65 Min:Max −143.9:186.8 −517.1:199.3 LSMean (SE)^(a) −1.01 (4.080) −10.36 (3.397) LS Mean difference (SE) vs.Placebo^(a) −9.36 (3.678) 95% CI (−16.586 to −2.124) p-value 0.0114 LOCF= Last observation carried forward. ^(a)Analysis of covariance (ANCOVA)model with treatment groups (lixisenatide and placebo), randomizationstrata of screening HbA1c (<8.0, ≥8.0%), randomization strata ofmetformin use at screening (Yes, No), and country as fixed effects andbaseline fasting plasma insulin value as a covariate. The analysisincludes measurements before the introduction of rescue medication andup to 1 day after the last dose of the double-blind investigationalproduct injection on or before Visit 12 (Week 24), or Day 169 if Visit12 (Week 24) is not available. Patients with both baseline and Week 24(LOCF) measurements are included.

6.3 Safety

An overview of the adverse events observed during the on-treatmentperiod for the whole study is provided in Table 17. The proportions ofpatients who experienced treatment emergent adverse events (TEAEs) were87.9% in the lixisenatide group and 83.2% in the placebo group. Nopatients in the lixisenatide group died, but 2 patients in the placebogroup died. One had a treatment emergent acute myocardial infarctionleading to death and the other died due to a post-treatment AE (endstage debility) following respiratory failure with multiorgan failure.The percentage of patients who had serious TEAEs was lower in thelixisenatide group (7.4%) than in the placebo group (9.3%). Higherpercentage of patients in the lixisenatide group (9.3%) experiencedTEAEs leading to treatment discontinuation than in the placebo group(7.5%). Table 18, Table 19, and Table 20 summarize TEAEs leading todeath, serious TEAEs, and TEAEs leading to treatment discontinuation byprimary SOC, HLGT, HLT and PT, respectively. The most common TEAEleading to treatment discontinuation was nausea in the lixisenatidegroup (6 patients [1.9%]) while no patient discontinued treatment due tonausea in the placebo group.

Table 30 in the appendix presents the incidences of TEAEs during theon-treatment period of the whole study occurring in at least 1% ofpatients in any treatment group. Nausea was the most frequently reportedTEAE in the lixisenatide group (84 patients [26.0%] versus 22 [13.7%]for placebo). The second most frequently reported TEAE in thelixisenatide group was nasopharyngitis (53 [16.4%] versus 24 [14.9%] forplacebo) followed by headache (43 [13.3%] versus 19 [11.8%] forplacebo), upper respiratory tract infection (41 [12.7%] versus 18[11.2%] for placebo), diarrhoea (35 [10.8%] versus 23 [14.3%] forplacebo), and dizziness (33 [10.2%] versus 13 [8.1%] for placebo).

TABLE 17 Overview of adverse event profile:treatment emergent adverseevents during the on-treatment period of the whole study-Safetypopulation Placebo Lixisenatide (N = 161) (N = 323) Patients with anyTEAE 134 (83.2%) 284 (87.9%) Patients with any serious TEAE  15 (9.3%) 24 (7.4%) Patients with any TEAE leading to death  1 (0.6%)  0 Patientswith any TEAE leading to  12 (7.5%)  30 (9.3%) permanent treatmentdiscontinuation TEAE: Treatment Emergent Adverse Event n (%) = numberand percentage of patients with at least one adverse event Note:on-treatment period of the whole study = the time from the first dose ofdouble-blind study medication up to 3 days after the last doseadministration

TABLE 18 Number (%) of patients experiencing TEAE(s) leading to death byprimary SOC, HLGT, HLT, and PT during the on-treatment period of thewhole study-Safety population PRIMARY SYSTEM ORGAN CLASS HLGT: HighLevel Group Term HLT: High Level Term Placebo Lixisenatide PreferredTerm (N = 161) (N = 323) CARDIAC DISORDERS 1 (0.6%) 0 HLGT: Coronaryartery disorders 1 (0.6%) 0 HLT: Ischaemic coronary artery disorders 1(0.6%) 0 Acute myocardial infarction 1 (0.6%) 0 TEAE: Treatment EmergentAdverse Event, SOC: System Organ Class, HLGT: High Level Group Term,HLT: High Level Term, PT: Preferred Term. MedDRA. version: 14.0. n (%) =number and percentage of patients with at least one TEAE leading todeath. Note: on-treatment period of the whole study = the time from thefirst dose of double-blind study medication up to 3 days after the lastdose administration. Table sorted by SOC internationally agreed orderand HLGT, HLT, PT alphabetic order.

TABLE 19 Number (%) of patients experiencing serious TEAE presented byprimary SOC, HLGT, HLT, and PT during the on-treatment period of thewhole study-Safety population PRIMARY SYSTEM ORGAN CLASS HLGT: HighLevel Group Term HLT: High Level Term Placebo Lixisenatide PreferredTerm (N = 161) (N = 323) Any class 15 (9.3%) 24 (7.4%) INFECTIONS ANDINFESTATIONS  3 (1.9%)  5 (1.5%) HLGT: Bacterial infectious disorders  1(0.6%)  0 HLT: Bacterial infections NEC  1 (0.6%)  0 Cellulitis  1(0.6%)  0 HLGT: Infections-pathogen unspecified  3 (1.9%)  5 (1.5%) HLT:Abdominal and gastrointestinal infections  0  1 (0.3%) Appendicitis  0 1 (0.3%) HLT: Lower respiratory tract and lung infections  3 (1.9%)  2(0.6%) Bronchitis  1 (0.6%)  1 (0.3%) Pneumonia  2 (1.2%)  1 (0.3%) HLT:Skin structures and soft tissue infections  0  1 (0.3%) Diabetic footinfection  0  1 (0.3%) HLT: Urinary tract infections  0  1 (0.3%)Urinary tract infection  0  1 (0.3%) NEOPLASMS BENIGN, MALIGNANT ANDUNSPECIFIED  1 (0.6%)  1 (0.3%) (INCL CYSTS AND POLYPS) HLGT:Hepatobiliary neoplasms malignant and unspecified  1 (0.6%)  0 HLT: Bileduct neoplasms malignant  1 (0.6%)  0 Bile duct cancer  1 (0.6%)  0HLGT: Respiratory and mediastinal neoplasms malignant and  0  1 (0.3%)unspecified HLT: Non-small cell neoplasms malignant of the respiratory 0  1 (0.3%) tract cell type specified Non-small cell lung cancer  0  1(0.3%) METABOLISM AND NUTRITION DISORDERS  1 (0.6%)  0 HLGT: Glucosemetabolism disorders (incl diabetes mellitus)  1 (0.6%)  0 HLT:Hyperglycaemic conditions NEC  1 (0.6%)  0 Hyperglycaemia  1 (0.6%)  0NERVOUS SYSTEM DISORDERS  1 (0.6%)  3 (0.9%) HLGT: Central nervoussystem vascular disorders  0  2 (0.6%) HLT: Central nervous systemhaemorrhages and  0  1 (0.3%) cerebrovascular accidents Cerebralinfarction  0  1 (0.3%) HLT: Transient cerebrovascular events  0  1(0.3%) Transient ischaemic attack  0  1 (0.3%) HLGT: Mental impairmentdisorders  1 (0.6%)  0 HLT: Memory loss (excl dementia)  1 (0.6%)  0Memory impairment  1 (0.6%)  0 HLGT: Spinal cord and nerve rootdisorders  0  1 (0.3%) HLT: Lumbar spinal cord and nerve root disorders 0  1 (0.3%) Sciatica  0  1 (0.3%) EYE DISORDERS  0  2 (0.6%) HLGT:Ocular infections, irritations and inflammations  0  1 (0.3%) HLT:Retinal, choroid and vitreous infections and  0  1 (0.3%) inflammationsMacular oedema  0  1 (0.3%) HLGT: Ocular structural change, deposit anddegeneration NEC  0  1 (0.3%) HLT: Retinal structural change, depositand degeneration  0  1 (0.3%) Retinal detachment  0  1 (0.3%) HLGT:Retina, choroid and vitreous haemorrhages and vascular  0  2 (0.6%)disorders HLT: Choroid and vitreous haemorrhages and vascular  0  1(0.3%) disorders Vitreous haemorrhage  0  1 (0.3%) HLT: RetinopathiesNEC  0  1 (0.3%) Diabetic retinopathy  0  1 (0.3%) CARDIAC DISORDERS  4(2.5%)  3 (0.9%) HLGT: Cardiac valve disorders  1 (0.6%)  0 HLT: Mitralvalvular disorders  1 (0.6%)  0 Mitral valve incompetence  1 (0.6%)  0HLGT: Coronary artery disorders  3 (1.9%)  3 (0.9%) HLT: Coronary arterydisorders NEC  1 (0.6%)  2 (0.6%) Arteriosclerosis coronary artery  0  1(0.3%) Coronary artery disease  1 (0.6%)  1 (0.3%) HLT: Ischaemiccoronary artery disorders  2 (1.2%)  1 (0.3%) Acute coronary syndrome  0 1 (0.3%) Acute myocardial infarction  1 (0.6%)  0 Angina unstable  1(0.6%)  0 VASCULAR DISORDERS  0  2 (0.6%) HLGT: Decreased andnonspecific blood pressure disorders and  0  1 (0.3%) shock     HLT:Circulatory collapse and shock  0  1 (0.3%) Shock haemorrhagic  0  1(0.3%) HLGT: Embolism and thrombosis  0  1 (0.3%) HLT: Peripheralembolism and thrombosis  0  1 (0.3%) Blue toe syndrome  0  1 (0.3%)RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS  1 (0.6%)  1 (0.3%)HLGT: Lower respiratory tract disorders (excl obstruction and  1 (0.6%) 0 infection) HLT: Lower respiratory tract inflammatory and immunologic 1 (0.6%)  0 conditions Pneumonitis  1 (0.6%)  0 HLGT: Respiratorydisorders NEC  0  1 (0.3%) HLT: Respiratory failures (excl neonatal)  0 1 (0.3%) Acute respiratory failure  0  1 (0.3%) GASTROINTESTINALDISORDERS  1 (0.6%)  3 (0.9%) HLGT: Abdominal hernias and otherabdominal wall conditions  0  2 (0.6%) HLT: Umbilical hernias  0  2(0.6%) Umbilical hernia  0  2 (0.6%) HLGT: Gastrointestinal signs andsymptoms  1 (0.6%)  0 HLT: Gastrointestinal and abdominal pains (excloral and  1 (0.6%)  0 throat) Abdominal pain  1 (0.6%)  0 HLGT:Peritoneal and retroperitoneal conditions  0  1 (0.3%) HLT: Peritonealand retroperitoneal haemorrhages  0  1 (0.3%) Peritoneal haemorrhage  0 1 (0.3%) HEPATOBILIARY DISORDERS  0  1 (0.3%) HLGT: Gallbladderdisorders  0  1 (0.3%) HLT: Cholecystitis and cholelithiasis  0  1(0.3%) Cholecystitis chronic  0  1 (0.3%) MUSCULOSKELETAL AND CONNECTIVETISSUE  1 (0.6%)  3 (0.9%) DISORDERS HLGT: Joint disorders  0  3 (0.9%)HLT: ArthropathiesNEC  0  1 (0.3%) Neuropathic arthropathy  0  1 (0.3%)HLT: Crystal arthropathic disorders  0  1 (0.3%) Gouty arthritis  0  1(0.3%) HLT: Osteoarthropathies  0  1 (0.3%) Osteoarthritis  0  1 (0.3%)HLGT: Musculoskeletal and connective tissue deformities (incl  1 (0.6%) 0 intervertebral disc disorders) HLT: Spine and neck deformities  1(0.6%)  0 Spinal column stenosis  1 (0.6%)  0 RENAL AND URINARYDISORDERS  0  1 (0.3%) HLGT: Urolithiases  0  1 (0.3%) HLT: Renallithiasis  0  1 (0.3%) Stag horn calculus  0  1 (0.3%) GENERAL DISORDERSAND ADMINISTRATION SITE  0  3 (0.9%) CONDITIONS HLGT: General systemdisorders NEC  0  3 (0.9%) HLT: Pain and discomfort NEC  0  3 (0.9%)Non-cardiac chest pain  0  3 (0.9%) INVESTIGATIONS  3 (1.9%)  0 HLGT:Endocrine investigations (incl sex hormones)  1 (0.6%)  0 HLT:Gastrointestinal, pancreatic and APUD hormone  1 (0.6%)  0 analysesBlood calcitonin increased  1 (0.6%)  0 HLGT: Gastrointestinalinvestigations  1 (0.6%)  0 HLT: Gastrointestinal and abdominal imagingprocedures  1 (0.6%)  0 Colonoscopy  1 (0.6%)  0 HLGT: Physicalexamination topics  1 (0.6%)  0 HLT: Physical examination procedures  1(0.6%)  0 Weight decreased  1 (0.6%)  0 INJURY, POISONING AND PROCEDURALCOMPLICATIONS  1 (0.6%)  3 (0.9%) HLGT: Bone and joint injuries  1(0.6%)  2 (0.6%) HLT: Fractures and dislocations NEC  0  1 (0.3%)Multiple fractures  0  1 (0.3%) HLT: Limb injuries NEC (incl traumaticamputation)  1 (0.6%)  0 Meniscus lesion  1 (0.6%)  0 HLT: Lower limbfractures and dislocations  0  1 (0.3%) Foot fracture  0  1 (0.3%) HLGT:Injuries NEC  0  1 (0.3%) HLT: Abdominal injuries NEC  0  1 (0.3%)Abdominal injury  0  1 (0.3%) HLT: Non-site specific injuries NEC  0  1(0.3%) Injury  0  1 (0.3%) SURGICAL AND MEDICAL PROCEDURES  2 (1.2%)  2(0.6%) HLGT: Vascular therapeutic procedures  2 (1.2%)  2 (0.6%) HLT:Arterial therapeutic procedures (excl aortic)  2 (1.2%)  2 (0.6%)Coronary angioplasty  0  1 (0.3%) Coronary artery bypass  2 (1.2%)  0Percutaneous coronary intervention  0  1 (0.3%) TEAE: Treatment EmergentAdverse Event, SOC: System Organ Class, HLGT: High Level Group Term,HLT: High Level Term, PT: Preferred Term. MedDRA version: 14.0. n (%) =number and percentage of patients with at least one serious TEAE. Note:on-treatment period of the whole study = the time from the first dose ofdouble-blind study medication up to 3 days after the last doseadministration. Table sorted by SOC internationally agreed order andHLGT, HLT, PT alphabetic order.

TABLE 20 Number (%) of patients experiencing TEAE(s) leading topermanent treatment discontinuation by primary SOC, HLGT, HLT, and PTduring the on-treatment period of the whole study-Safety populationPRIMARY SYSTEM ORGAN CLASS BLGT: High Level Group Term BLT: High LevelTerm Placebo Lixisenatide Preferred Term (N = 161) (N = 323) Any class12 (7.5%) 30 (9.3%) INFECTIONS AND INFESTATIONS  0  1 (0.3%) HLGT:Bacterial infectious disorders  0  1 (0.3%) HLT: Bacterial infectionsNBC  0  1 (0.3%) Cellulitis  0  1 (0.3%) METABOLISM AND NUTRITIONDISORDERS  1 (0.6%)  0 HLGT: Appetite and general nutritional disorders 1 (0.6%)  0 HLT: Appetite disorders  1 (0.6%)  0 Decreased appetite  1(0.6%)  0 PSYCHIATRIC DISORDERS  0  2 (0.6%) HLGT: Anxiety disorders andsymptoms  0  2 (0.6%) HLT: Panic attacks and disorders  0  2 (0.6%)Panic attack  0  2 (0.6%) NERVOUS SYSTEM DISORDERS  1 (0.6%)  5 (1.5%)HLGT: Central nervous system vascular disorders  0  1 (0.3%) HLT:Central nervous system haemorrhages and  0  1 (0.3%) cerebrovascularaccidents Cerebral infarction  0  1 (0.3%) HLGT: Headaches  0  2 (0.6%)HLT: Headaches NEC  0  2 (0.6%) Headache  0  2 (0.6%) HLGT: Mentalimpairment disorders  1 (0.6%)  0 HLT: Memory loss (excl dementia)  1(0.6%)  0 Memory impairment  1 (0.6%)  0 HLGT: Neurological disordersNEC  0  3 (0.9%) HLT: Neurological signs and symptoms NEC  0  3 (0.9%)Dizziness  0  3 (0.9%) EYE DISORDERS  0  1 (0.3%) HLGT: Vision disorders 0  1 (0.3%) HLT: Partial vision loss  0  1 (0.3%) Visual acuity reduced 0  1 (0.3%) EAR AND LABYRINTH DISORDERS  0  1 (0.3%) HLGT: Hearingdisorders  0  1 (0.3%) HLT: Hearing losses  0  1 (0.3%) Deafnessbilateral  0  1 (0.3%) CARDIAC DISORDERS  2 (1.2%)  1 (0.3%) HLGT:Cardiac arrhythmias  1 (0.6%)  0 HLT: Supraventricular arrhythmias  1(0.6%)  0 Atrial fibrillation  1 (0.6%)  0 HLGT: Cardiac valve disorders 1 (0.6%)  0 HLT: Mitral valvular disorders  1 (0.6%)  0 Mitral valveincompetence  1 (0.6%)  0 HLGT: Coronary artery disorders  1 (0.6%)  1(0.3%) HLT: Ischaemic coronary artery disorders  1 (0.6%)  1 (0.3%)Acute myocardial infarction  1 (0.6%)  0 Myocardial ischaemia  0  1(0.3%) RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS  1 (0.6%)  2(0.6%) HLGT: Respiratory disorders NEC  1 (0.6%)  2 (0.6%) HLT:Breathing abnormalities  0  1 (0.3%) Dyspnoea  0  1 (0.3%) HLGT:Coughing and associated symptoms  1 (0.6%)  0 Cough  1 (0.6%)  0 HLT:Upper respiratory tract signs and symptoms  0  1 (0.3%) Throat tightness 0  1 (0.3%) GASTROINTESTINAL DISORDERS  1 (0.6%) 10 (3.1%) HLGT:Gastrointestinal motility and defaecation conditions  0  1 (0.3%) HLT:Diarrhoea (excl infective)  0  1 (0.3%) Diarrhoea  0  1 (0.3%) HLGT:Gastrointestinal signs and symptoms  1 (0.6%)  8 (2.5%) HLT: Flatulence,bloating and distension  0  2 (0.6%) Abdominal distension  0  1 (0.3%)Flatulence  0  1 (0.3%) HLT: Gastrointestinal and abdominal pains (excloral and  1 (0.6%)  0 throat) Abdominal pain lower  1 (0.6%)  0 HLT:Nausea and vomiting symptoms  0  7 (2.2%) Nausea  0  6 (1.9%) Vomiting 0  2 (0.6%) HLGT: Gastrointestinal ulceration and perforation  0  1(0.3%) HLT: Peptic ulcers and perforation  0  1 (0.3%) Peptic ulcer  0 1 (0.3%) SKIN AND SUBCUTANEOUS TISSUE DISORDERS  1 (0.6%)  3 (0.9%)HLGT: Angioedema and urticaria  0  1 (0.3%) HLT: Urticarias  0  1 (0.3%)Urticaria  0  1 (0.3%) HLGT: Epidermal and dermal conditions  1 (0.6%) 2 (0.6%) HLT: Dermatitis and eczema  1 (0.6%)  2 (0.6%) Dermatitis  0 1 (0.3%) Dermatitis allergic  0  1 (0.3%) Eczema  1 (0.6%)  0MUSCULOSKELETAL AND CONNECTIVE TISSUE  0  3 (0.9%) DISORDERS HLGT: Jointdisorders  0  1 (0.3%) HLT: Joint related signs and symptoms  0  1(0.3%) Arthralgia  0  1 (0.3%) HLGT: Muscle disorders  0  1 (0.3%) HLT:Muscle pains  0  1 (0.3%) Myalgia  0  1 (0.3%) HLGT: Musculoskeletal andconnective tissue disorders NEC  0  1 (0.3%) HLT: Musculoskeletal andconnective tissue pain and  0  1 (0.3%) discomfort Pain in extremity  0 1 (0.3%) GENERAL DISORDERS AND ADMINISTRATION SITE  1 (0.6%)  5 (1.5%)CONDITIONS HLGT: General system disorders NEC  1 (0.6%)  5 (1.5%) HLT:Asthenic conditions  0  2 (0.6%) Asthenia  0  1 (0.3%) Fatigue  0  1(0.3%) HLT: Oedema NEC  1 (0.6%)  2 (0.6%) Oedema  0  1 (0.3%) Oedemaperipheral  1 (0.6%)  1 (0.3%) HLT: Pain and discomfort NEC  0  1 (0.3%)Non-cardiac chest pain  0  1 (0.3%) INVESTIGATIONS  4 (2.5%)  4 (1.2%)HLGT: Endocrine investigations (incl sex hormones)  2 (1.2%)  1 (0.3%)HLT: Gastrointestinal, pancreatic and APUD hormone  2 (1.2%)  1 (0.3%)analyses Blood calcitonin increased  2 (1.2%)  1 (0.3%) HLGT:Gastrointestinal investigations  1 (0.6%)  1 (0.3%) HLT: Digestiveenzymes  1 (0.6%)  1 (0.3%) Blood amylase increased  1 (0.6%)  1 (0.3%)Lipase increased  1 (0.6%)  1 (0.3%) HLGT: Metabolic, nutritional andblood gas investigations  0  1 (0.3%) HLT: Carbohydrate toleranceanalyses (incl diabetes)  0  1 (0.3%) Glycosylated haemoglobin increased 0  1 (0.3%) HLGT: Physical examination topics  1 (0.6%)  1 (0.3%) HLT:Physical examination procedures  1 (0.6%)  1 (0.3%) Weight increased  1(0.6%)  1 (0.3%) INJURY, POISONING AND PROCEDURAL COMPLICATIONS  0  1(0.3%) HLGT: Injuries NEC  0  1 (0.3%) HLT: Abdominal injuries NEC  0  1(0.3%) Abdominal injury  0  1 (0.3%) TEAE: Treatment Emergent AdverseEvent, SOC: System Organ Class, HLGT: High Level Group Term, HLT: HighLevel Term, PT: Preferred Term. MedDRA version: 14.0. n (%) = number andpercentage of patients with at least one TEAE leading to permanenttreatment discontinuation. Note: on-treatment period of the whole study= the time from the first dose of double-blind study medication up to 3days after the last dose administration. Table sorted by SOCinternationally agreed order and HLGT, HLT, PT alphabetic order.

During the on-treatment period of the whole study, a total of 36patients (27 in the lixisenatide group and 9 in the placebo group)reported TEAEs on a pre-specified AE form for “symptomatichypoglycaemia”. Among them, 23 (7.1%) patients in the lixisenatide grouphad symptomatic hypoglycemia per protocol definition, compared to 7(4.3%) in the placebo group (Table 21). None of the symptomatichypoglycemia events were severe in intensity. The events in theremaining 6 patients (4 in the lixisenatide group and 2 in the placebogroup) did not meet the protocol-specified symptomatic hypoglycemiadefinition due to the associated glucose values being >60 mg/dL or nosymptoms reported.

Twenty-two (6.8%) patients in the lixisenatide group and 8 (5.0%) in theplacebo group experienced injection site reaction AEs (Table 22). Theinjection site reaction AEs were identified by searching the term“injection site” in either the PTs coded from the investigator reportedterms or the PTs from the ARAC diagnosis after the allergic reactionadjudication. None of these injection site reaction events were seriousor severe in intensity or led to IP discontinuation.

A total of 56 possible allergic events were reported in 39 patients byinvestigators and were sent to ARAC for adjudication during theon-treatment period of the whole study. Of these, 19 events in 12patients (9 [2.8%] patients in the lixisenatide group and 3 [1.9%] inthe placebo group) were adjudicated as allergic reactions by ARAC, whichincluded 5 events in 3 patients in the lixisenatide group (1 withallergic dermatitis, 1 with urticaria, and 1 with angioedema,anaphylactic reaction, and allergic conjunctivitis) adjudicated aspossibly related to IP. (Table 23).

-   -   Patient 124713001 (lixisenatide group): with a medical history        of urticaria and multiple allergies, as well as pruritus, on Day        258 (7 Nov. 2009) after start of IP experienced a non-serious        TEAE of WELT FROM NEEDLE (coded to PT “injection site        urticaria”) of mild intensity. No corrective treatment was given        and the event was recovered after 7 days. The event was not        considered as related to IP. From Day 264 until Day 368 after        start of IP intake the patient had intermittently stopped IP        administration for one day. From day 369 to day 386 the patient        did not administer the IP. From day 387 to day 393 the patient        again injected 20 μg of IP each day. Then, again IP        administration was stopped for 2 days and injected for the last        time on day 396. IP was permanently stopped due to a non-serious        TEAE of mild intensity REOCCURING WELTS AFTER RESTARTING STUDY        MEDICATION (coded to PT “urticaria”) on day 396 day after start        of IP administration. This event was considered as related to        IP. The event resolved 11 days after last administration of IP        without any corrective treatment. Both events were sent to ARAC        for adjudication but only the 2nd event was adjudicated by ARAC        as an allergic reaction urticaria (hives), possibly related to        the IP.    -   Patient 642701006 (lixisenatide group): This patient without a        history of allergy experienced on Day 163 (1 Oct. 2009) after        start of IP a non-serious TEAE of ALLERGY (coded to PT        “hypersensitivity”) of mild intensity. Thirty minutes after        injection of the IP, the patient complained about generalized        itch and redness of the eyes, which spontaneously disappeared        without treatment. The event resolved the same day. On day 169        after start of IP, a non-serious TEAE of ALLERGIC DERMATITIS        (coded to PT “dermatitis allergic”) of moderate intensity was        reported. Twenty-five minutes after administration of IP, the        patient complained about generalized itch, swelling of eyes and        tongue and swelling at the injection site. The event resolved on        the same day. Oral loratadine was started on day 169 after start        of IP and given as corrective treatment for 7 days. On day 170        after start of IP, another non-serious TEAE of ALLERGIC        DERMATITIS (coded to PT “dermatitis allergic”) of moderate        intensity was reported and resolved the same day. Immediately        after administration of IP, the patient complained about        swelling at the injection site, generalized itch, generalized        rush, swelling of the eyes and tongue, nausea. All 3 events were        considered as related to IP and IP was permanently stopped due        to the third event after day 170. The 3 events were adjudicated        by ARAC as allergic reactions (allergic conjunctivitis,        angioedema and anaphylactic reaction respectively), possibly        related to the IP.    -   Patient 840864001 (lixisenatide group): with a medical history        of allergic rhinitis, pollen allergies, dust allergies, swelling        (angioedema), drug allergies, rush and dermatitis, experienced a        non-serious TEAE of DERMATITIS ON BILATERAL ARMS AND ABDOMEN        (coded to PT “dermatitis”) of moderate intensity on the third        day after start of IP administration. Clindamycin was given as        corrective treatment for three days. IP administration was        temporarily stopped on Day 5 until Day 8 after start of IP        administration. A re-challenge with IP on Day 9 to Day 13 caused        a worsening on the abdominal wall. The event was considered as        related to IP and the IP was permanently stopped after day 13.        The event resolved 12 days (21 Dec. 2009) after permanent        discontinuation from IP. This TEAE was adjudicated by ARAC as an        allergic reaction (allergic dermatitis), possibly related to IP.

No event was adjudicated by ARAC as possibly related to IP in theplacebo group. Per protocol, any increase in amylase and/or lipase abovetwice the upper limit of normal range (ULN) that had been confirmed by arepeat measurement was to be monitored and documented on a pre-specifiedAE form for “suspected pancreatitis”. During the on-treatment period ofthe whole study, 2 (0.6%) patients in the lixisenatide group and 2(1.2%) in the placebo group reported TEAEs with the pre-specified AEform (Table 24). No case of pancreatitis was diagnosed or reported.

Patients who had at least one value of lipase or amylase≥3 ULN duringthe on-treatment period are summarized in (Table 25). A total of 7patients experienced elevated lipase (3ULN): 5 [1.6%] in thelixisenatide group, 2 [1.3%] in the placebo group. No one had elevatedamylase ≥3ULN.

Per protocol, any calcitonin value >20 μg/mL confirmed by a repeatmeasurement was to be monitored and reported on the pre-specified AEform for “increased calcitonin 20 μg/mL”. During the on-treatment periodof the whole study, 9 (2.8%) patients in the lixisenatide group and 4(2.5%) in the placebo group reported increased blood calcitonin on thepre-specified AE form (Table 26). Among them, 8 out of 9 patients in thelixisenatide group had calcitonin values >20 but <50 ng/L and 1 patienthad a calcitonin value ≥50 ng/L, whereas in the placebo group 3 out of 4patients had calcitonin values >20 but <50 ng/L and 1 patient hadcalcitonin values 50 ng/L. One additional patient in the lixisenatidegroup reported a post-treatment AE on the pre-specified adverse eventform for “increased calcitonin 20 μg/mL” with calcitonin values ≥20 but<50 ng/L. Two patients in the lixisenatide group and 1 patient in theplacebo group reported AEs that were coded to PT “thyroid neoplasm”.

-   -   Patient 642706001 (lixisenatide group): a non-smoker, without a        history of thyroid disease and without renal insufficiency,        experienced a non-serious adverse event LEFT THYROID LOBE NODULE        of mild intensity twenty-four days after last administration of        IP. No thyroid medication was given. The event was considered as        not related to IP. At Visit 15, 255 days after start of IP,        calcitonin was measured for the first time and was 16.4 ng/L. At        the last day of IP, calcitonin was 22.2 ng/L and in the re-test        one week later 18.9 ng/L.    -   Patient 840738004 (lixisenatide group): a former smoker of 35        years, without a history of thyroid disease and without renal        insufficiency experienced a non serious TEAE of 6 mm THYROID        NODULE LEFT LOBE of mild intensity 39 days after first intake of        IP. No thyroid medication was given. A thyroid ultrasound 177        days after first intake of IP confirmed a 7×3 mm nodule in the        left lobe. The first calcitonin at start of IP intake was 19.7        ng/L. Two-hundred sixty-two days after first intake of IP a        non-serious TEAE ELEVATED CALCITONIN of mild intensity was        reported on the specific pages for increased calcitonin due to a        calcitonin value of 20.1 ng/L. The event ELEVATED CALCITONIN was        resolved without treatment 376 days after first intake of IP.        Nine days before, calcitonin was 16.3 ng/L. At the last day of        IP intake, calcitonin was 19.4 ng/L. Both events were considered        as not related to IP.

Patients with at least one serum calcitonin measurement during theon-treatment period of the whole study are summarized in Table 27according to the 4 pre-defined categories of calcitonin level atbaseline. A total of 17 patients had calcitonin values 20 ng/L duringthe on-treatment period of the whole study: 11 (3.7%) patients in thelixisenatide group, 6 (4.2%) patients in the placebo group. Among them,13 patients (9 for lixisenatide and 4 for placebo) reported a TEAE withthe pre-specified AE form as described above. Two patients in eachtreatment group had at least 1 calcitonin value 20 ng/L but did notreport a TEAE with the pre-specified AE form during the on-treatmentperiod of the whole study. For one patient who had multiple values ≥20but <50 ng/L in the placebo group this was due to measurements donebefore protocol amendment 4 which required the retesting. For the other3 patients this was because of an unconfirmed calcitonin elevation: 1patient in each group had a single value ≥20 but <50 ng/L and 1 in thelixisenatide group had a single value ≥50 ng/L, but their other pre-and/or post-measurements were <20 ng/L. Since calcitonin measurementswere implemented in a protocol amendment after most patients werealready randomized in this study. Therefore, baseline calcitonin valueswere not available for most patients.

One patient in the placebo group and 2 patients in the lixisenatidegroup had a calcitonin value >50 ng/L (Table 27).

-   -   Patient 840782004 (lixisenatide group): a non-smoker, without        thyroid diseases in the medical history and without renal        insufficiency, on the day of the first IP administration (3        Aug. 2009) calcitonin was 37.8 ng/L and a non-serious TEAE of        CALCITONIN ELEVATION of mild intensity was reported one day        later. IP was continued. No corrective treatment was given. A        thyroid ultrasound was not performed. The event was considered        as related to IP. The further calcitonin values during the study        were 64.2, 19.3, 50, 36.5 and on Day 260 (19 Apr. 2010) after        start of IP it was 29.6 ng/L. Forty-three days (24 Aug. 2010)        after permanent discontinuation of IP (due to lack of efficacy),        calcitonin was 48.1 ng/L.    -   Patient 040702004 (lixisenatide group): had a calcitonin value        of 104 ng/L at one visit during the study. At the re-test 14        days later, calcitonin was 3 ng/L. Because at all earlier and        later visits during the study calcitonin values were between        <0.6 ng/L and 3 ng/L no TEAE referring to calcitonin was        reported and no further thyroid investigation performed.

TABLE 21 Summary of symptomatic hypoglycemia during the on-treatmentperiod of the whole study- Safety population Placebo Lixisenatide Type(N = 161) (N = 323) Total patient years 227.6 493.9 Any symptomatichypoglycemia Number of patients with events, n (%) 7 (4.3%) 23 (7.1%)Number of patients with events per 100 patient years^(a) 3.1 4.7 Bloodglucose <60 mg/dL Number of patients with events, n (%) 7 (4.3%) 17(5.3%) Number of patients with events per 100 patient years^(a) 3.1 3.4No blood glucose reported Number of patients with events, n (%) 0 9(2.8%) Number of patients with events per 100 patient years^(a) 0.0 1.8^(a)Calculated as (number of patients with events * 100 divided by totalexposure + 3 days in patient years). Symptomatic hypoglycemia =Symptomatic hypoglycemia as defined per protocol Note: on-treatmentperiod of the whole study = the time from the first dose of double-blindstudy medication up to 3 days after the last dose administration.

TABLE 22 Number (%) of patients experiencing injection site reactionsduring the on-treatment period of the whole study-Safety populationEvent source Placebo Lixisenatide Preferred Term (N = 161) (N = 323) Anyinjection site reactions 8 (5.0%) 22 (6.8%) Investigator reported PTs 7(4.3%) 22 (6.8%) Injection site pain 4 (2.5%)  5 (1.5%) Injection sitehaematoma 3 (1.9%)  8 (2.5%) Injection site reaction 1 (0.6%)  4 (1.2%)Injection site swelling 1 (0.6%)  0 Injection site erythema 0  5 (1.5%)Injection site haemorrhage 0  1 (0.3%) Injection site hypersensitivity 0 1 (0.3%) Injection site mass 0  1 (0.3%) Injection site pruritus 0  4(1.2%) Injection site rash 0  1 (0.3%) Injection site urticaria 0  2(0.6%) PTs by ARAC diagnosis 3 (1.9%)  7 (2.2%) Injection site reaction3 (1.9%)  7 (2.2%) ARAC = Allergic Reaction Assessment Committee. Note:on-treatment period of the whole study = the time from the first dose ofdouble-blind study medication up to 3 days after the last doseadministration.

TABLE 23 Number (%) of patients with events adjudicated as an allergicreaction by ARAC during the on-treatment period of the wholestudy-Safety population Relationship to MedDRA coded study treatmentterm (PT) for ARAC Placebo Lixisenatide (by ARAC) ARAC diagnosisdiagnosis (N = 161) (N = 323) All Events adjudicated 3 (1.9%) 9 (2.8%)as an allergic reaction byARAC Anaphylactic reaction Anaphylacticreaction 0 1 (0.3%) Angioedema Angioedema 1 (0.6%) 1 (0.3%)Conjunctivitis allergic Allergic conjunctivitis 0 1 (0.3%)Conjunctivitis Conjunctivitis 0 1 (0.3%) Dermatitis allergic Allergicdermatitis 0 1 (0.3%) Dermatitis contact Allergic contact 1 (0.6%) 2(0.6%) dermatitis Dermatitis contact Allergic contact 0 1 (0.3%)dermatitis (poison ivy) Dermatitis contact Contact dermatitis 1 (0.6%) 0(poison ivy) Drug eruption Allergic dermatitis to 0 1 (0.3%) glypizidePruritus generalised Generalized itch 1 (0.6%) 0 Rhinitis allergicAllergic rhinitis 0 1 (0.3%) Rhinitis Rhinitis 0 1 (0.3%) UrticariaUrticaria (hives) 0 1 (0.3%) Related Events adjudicated 0 3 (0.9%) as anallergic reaction by ARAC Anaphylactic reaction Anaphylactic reaction 01 (0.3%) Angioedema Angioedema 0 1 (0.3%) Conjunctivitis allergicAllergic conjunctivitis 0 1 (0.3%) Dermatitis allergic Allergicdermatitis 0 1 (0.3%) Urticaria Urticaria (hives) 0 1 (0.3%) Not relatedEvents adjudicated 3 (1.9%) 6 (1.9%) as an allergic reaction by ARACAngioedema Angioedema 1 (0.6%) 0 Conjunctivitis Conjunctivitis 0 1(0.3%) Dermatitis contact Allergic contact 1 (0.6%) 2 (0.6%) dermatitisDermatitis contact Allergic contact 0 1 (0.3%) dermatitis (poison ivy)Dermatitis contact Contact dermatitis 1 (0.6%) 0 (poison ivy) Drugeruption Allergic dermatitis to 0 1 (0.3%) glypizide Pruritusgeneralised Generalized itch 1 (0.6%) 0 Rhinitis allergic Allergicrhinitis 0 1 (0.3%) Rhinitis Rhinitis 0 1 (0.3%) ARAC = AllergicReaction Assessment Committee. IP = Investigational Product. Note:on-treatment period of the whole study = the time from the first dose ofdouble-blind study medication up to 3 days after the last doseadministration.

TABLE 24 Number (%) of patients with a specific adverse event form forsuspected pancreatitis completed during the on-treatment period of thewhole study-Safety population Placebo Lixisenatide Preferred Term (N =161) (N = 323) Any 2 (1.2%) 2 (0.6%) Blood amylase increased 1 (0.6%) 2(0.6%) Lipase increased 2 (1.2%) 2 (0.6%) n (%) = number and percentageof patients with any cases reported on the AE form for suspectedpancreatitis along with complementary form. Note: on-treatment period ofthe whole study = the time from the first dose of double-blind studymedication up to 3 days after the last dose administration.

TABLE 25 Pancreatic enzymes: Number (%) of patients with abnormalities(PCSA) during the on-treatment period of the whole study according tobaseline PCSA status-Safety population Laboratory parameter Baseline ByPlacebo Lixisenatide PCSA criteria n/N1 (%) (N = 161) (N = 323) Lipase(IU/L) Total* ≥3ULN 2/160 (1.3%) 5/317 (1.6%) Normal/Missing ≥3ULN 2/159(1.3%) 5/317 (1.6%) Amylase (IU/L) Total* ≥3ULN 0/160 0/317Normal/Missing ≥3ULN 0/160 0/317 PCSA: Potentially ClinicallySignificant Abnormalities, ULN = Upper limit of normal. *Regardless ofbaseline. Note: on-treatment period of the whole study = the time fromthe first dose of double-blind study medication up to 3 days after thelast dose administration. The number (n) represents the subset of thetotal number of patients who met the criterion in question at leastonce. The denominator (/N1) for each parameter within a treatment groupis the number of patients for the treatment group who had that parameterassessed post-baseline by baseline PCSA status. Only the worsening ofthe worst case for each patient is presented by baseline status.

TABLE 26 Number (%) of patients with increased calcitonin during theon-treatment period of the whole study-Safety population PlaceboLixisenatide Preferred Term (N = 161) (N = 323) Any 4 (2.5%) 9 (2.8%)Blood calcitonin increased 4 (2.5%) 9 (2.8%) n (%) = number andpercentage of patients with any cases reported on the AE form forincreased calcitonin ≥20 ng/L. Note: on-treatment period of the wholestudy = the time from the first dose of double-blind study medication upto 3 days after the last dose administration.

TABLE 27 Serum calcitonin: Number (%) of patients by pre-definedcategories during the on-treatment period of the whole study accordingto baseline category-Safety population Laboratory criteria Baselinestatus Placebo Lhisenatide Post-baseline (N = 161) (N = 323) Calcitonin(ng/L) Total* ≤ULN 117/144 (81.3%) 265/303 (87.5%) >ULN-<20 ng/L 21/144(14.6%) 27/303  (8.9%) ≥20 ng/L-<50 ng/L 5/144  (3.5%) 9/303  (3.0%) ≥50ng/L 1/144  (0.7%) 2/303  (0.7%) Missing ≤ULN 72/83 (86.7%) 161/178(90.4%) >ULN-<20 ng/L 8/83  (9.6%) 12/178  (6.7%) ≥20 ng/L-<50 ng/L 3/83 (3.6%) 5/178  (2.8%) ≥50 ng/L 0/83 0/178 ≤ULN ≤ULN 44/53 (83.0%)104/110 (94.5%) >ULN-<20 ng/L 9/53 (17.0%) 5/110  (4.5%) ≥20 ng/L-<50ng/L 0/53 0/110 ≥50 ng/L 0/53 1/110  (0.9%) >ULN-<20 ng/L ≤ULN 1/5(20.0%) 0/12 >ULN-<20 ng/L 4/5 (80.0%) 10/12 (83.3%) ≥20 ng/L-<50 ng/L0/5 2/12 (16.7%) ≥50 ng/L 0/5 0/12 ≥20 ng/L-<50 ng/L ≤ULN 0/30/3 >ULN-<20 ng/L 0/3 0/3 ≥20 ng/L-<50 ng/L 2/3 (66.7%) 2/3 (66.7%) ≥50ng/L 1/3 (33.3%) 1/3 (33.3%) ≤50 ng/L ≤ULN 0/0 0/0 >ULN-<20 ng/L 0/0 0/0≥20 ng/L-<50 ng/L 0/0 0/0 ≥50 ng/L 0/0 0/0 ULN = Upper limit of normal*Regardless of baseline. Note: on-treatment period of the whole study =the time from the first dose of double-blind study medication up to 3days after the last dose administration. The numerator represents thenumber of patients who were in the pre-specified categories atpost-baseline in each baseline category. The denominator for eachparameter within a treatment group is the number of patients for thetreatment group who had that parameter assessed post-baseline bybaseline status. A patient is counted only in the worst category.

7 APPENDIX

TABLE 28 Number (%) of patients by total daily dose at the end oftitration-Safety population Dose at the Placebo Lixisenatide end oftitration (N = 161) (N = 323) 10 ug  1 (0.6%)  13 (4.0%) 15 μg  5 (3.1%) 21 (6.5%) 20 μg 155 (96.3%) 289 (89.5%) Dose = Dose of active drug orvolume-matched placebo. The scheduled visit for end of titration perprotocol would be Visit 5/Week 2. Note: Percentages are calculated usingthe number of safety patients as the denominator.

TABLE 29 Mean change in HbA1c (%) from baseline by visit mITT TreatmentObserved data Change from baseline Time point N Mean SD SE Median MinMax N Mean SD SE Median Min Max Placebo (N = 159) Screening 159 8.140.82 0.065 8.00 7.0 10.0 Baseline 159 8.06 0.79 0.063 7.90 6.5 10.2Week* 144 7.74 0.83 0.069 7.55 6.3 10.2 144 −0.31 0.75 0.062 −0.30 −2.22.3 Week 12 141 7.67 0.95 0.080 7.60 6.0 10.4 141 −0.39 0.89 0.075 −0.40−2.6 2.7 Week 24 123 7.44 0.86 0.077 7.30 5.5 10.1 123 −0.57 0.93 0.084−0.40 −4.0 1.6 Week 24 (LOCF) 148 7.59 0.96 0.079 7.40 5.5 10.4 148−0.46 1.00 0.082 −0.40 −4.0 2.5 Week 36 100 7.22 0.82 0.082 7.10 5.1 9.7100 −0.77 0.99 0.099 −0.70 −4.4 1.6 Week 44 90 7.16 0.73 0.077 7.10 5.38.9 90 −0.77 0.92 0.097 −0.70 −3.9 1.4 Week 52 86 7.17 0.75 0.081 7.205.5 8.9 86 −0.74 0.92 0.100 −0.70 −3.9 1.4 Week 60 80 7.22 0.76 0.0857.20 5.7 9.1 80 −0.67 0.97 0.109 −0.50 −3.8 1.6 Week 68 72 7.21 0.870.103 7.20 5.8 10.0 72 −0.66 1.03 0.121 −0.65 −3.6 1.5 Week 76 71 7.250.97 0.115 7.10 5.3 11.0 71 −0.62 1.07 0.127 −0.70 −3.9 2.0 Week 84 487.26 1.19 0.172 7.10 5.4 11.9 48 −0.58 1.11 0.160 −0.70 −2.7 2.9 Week 9230 7.13 0.78 0.143 7.15 5.2 9.9 30 −0.67 0.86 0.156 −0.75 −3.0 1.5 Week100 22 7.20 0.82 0.176 7.35 4.7 9.0 22 −0.69 0.78 0.167 −0.55 −2.4 0.9Week 108 8 7.31 0.67 0.238 7.50 6.3 8.2 8 −0.65 0.98 0.347 −0.60 −2.50.4 Week 116 4 7.55 0.70 0.352 7.45 6.8 8.5 4 −0.25 0.76 0.380 −0.25−1.0 0.5 Week 124 2 7.30 1.13 0.800 7.30 6.5 8.1 2 −0.50 0.85 0.600−0.50 −1.1 0.1 Week 132 1 6.70 NC NC 6.70 6.7 6.7 1 −0.90 NC NC −0.90−0.9 −0.9 Last on−treatment 148 7.74 1.09 0.090 7.70 4.7 11.9 148 −0.301.12 0.092 −0.30 −3.9 2.9 value Lixisenatide (N = 320) Screening 3198.15 0.83 0.046 8.00 7.0 10.0 Baseline 320 8.08 0.90 0.050 7.90 6.5 12.7Week 8 293 7.30 0.82 0.048 7.10 5.5 10.9 293 −0.78 0.80 0.047 −0.70 −6.03.2 Week 12 285 7.12 0.88 0.052 6.90 5.3 12.2 285 −0.97 0.93 0.055 −0.90−5.1 3.1 Week 24 276 6.92 0.82 0.050 6.80 5.3 11.3 276 −1.16 1.02 0.061−1.00 −5.4 3.1 Week 24 (LOCF) 308 7.06 0.96 0.055 6.90 5.3 11.3 308−1.02 1.09 0.062 −0.90 −5.4 3.5 Week 36 242 6.80 0.80 0.051 6.75 5.211.4 242 −1.23 1.03 0.066 −1.10 −5.7 2.3 Week 44 231 6.81 0.72 0.0476.80 5.3 9.4 231 −1.23 0.99 0.065 −1.10 −5.8 1.3 Week 52 223 6.84 0.730.049 6.80 5.2 9.4 223 −1.17 0.97 0.065 −1.00 −5.6 1.1 Week 60 203 6.810.67 0.047 6.80 5.1 9.1 203 −1.18 0.95 0.067 −1.00 −5.8 0.6 Week 68 2076.84 0.72 0.050 6.80 4.6 9.5 207 −1.17 1.07 0.075 −0.90 −6.1 2.1 Week 76194 6.87 0.74 0.053 6.80 4.8 9.5 194 −1.13 1.04 0.075 −1.05 −5.8 1.5Week 84 142 6.91 0.78 0.065 6.80 5.5 10.2 142 −1.04 1.05 0.088 −0.90−5.9 2.6 Week 92 114 6.96 0.72 0.068 6.90 5.2 9.0 114 −0.99 1.00 0.094−0.80 −6.0 2.1 Week 100 87 7.08 0.82 0.088 7.00 5.7 10.3 87 −0.97 1.110.119 −0.85 −6.1 2.1 Week 108 46 6.86 0.63 0.093 6.80 5.6 8.3 46 −1.260.97 0.143 −1.00 −3.9 0.8 Week 116 20 7.06 0.73 0.162 6.85 6.1 8.6 20−0.97 0.91 0.203 −0.80 −3.0 0.3 Week 124 6 7.47 1.11 0.455 7.55 6.1 8.86 −0.98 0.52 0.210 −0.95 −1.9 −0.5 Last on−treatment 308 7.33 1.09 0.0627.20 4.8 11.3 308 −0.75 1.20 0.068 −0.70 −6.0 3.5 value NC Notcomputable. LOCF = Last observation carried forward. Note: The analysisexcludes measurements obtained after the introduction of rescuemedication and/or after the treatment cessation plus 3 days. For Week 24(LOCF), the analysis includes measurements obtained up to 3 days afterthe last dose of the double−blind investigational product injection onor before Visit 12 (Week 24), or Day 169 if Visit 12 (Week 24) is notavailable.

TABLE 30 Number (%) of patients experiencing common TEAE(s) (PT ≥ 1% inany treatment group) presented by primary SOC, HLGT, HLT and PT duringthe on-treatment period of the whole study-Safety population PRIMARYSYSTEM ORGAN CLASS HLGT: High Level Group Term HLT: High Level TermPlacebo Lixisenatide Preferred Term (N = 161) (N = 323) Any class 134(83.2%) 284 (87.9%) INFECTIONS AND INFESTATIONS  77 (47.8%) 173 (53.6%)HLGT: Bacterial infectious disorders  12 (7.5%)  8 (2.5%) HLT: Bacterialinfections NEC  8 (5.0%)  8 (2.5%) Cellulitis  5 (3.1%)  6 (1.9%) HLT:Streptococcal infections  4 (2.5%)  0 Pharyngitis streptococcal  4(2.5%)  0 HLGT: Fungal infectious disorders  6 (3.7%)  10 (3.1%) HLT:Tinea infections  3 (1.9%)  3 (0.9%) Tinea pedis  3 (1.9%)  2 (0.6%)HLGT: Infections- pathogen unspecified  66 (41.0%) 152 (47.1%) HLGT:Abdominal and gastrointestinal infections  4 (2.5%)  11 (3.4%)Gastroenteritis  2 (1.2%)  8 (2.5%) HLT: Dental and oral soft tissueinfections  2 (1.2%)  7 (2.2%) Tooth abscess  2 (1.2%)  2 (0.6%) HLT:Ear infections  7 (4.3%)  6 (1.9%) Ear infection  6 (3.7%)  2 (0.6%)HLT: Infections NEC  2 (1.2%)  12 (3.7%) Localised infection  2 (1.2%) 1 (0.3%) Respiratory tract infection  0  5 (1.5%) HLT: Lowerrespiratory tract and lung infections  24 (14.9%)  28 (8.7%) Bronchitis 17 (10.6%)  25 (7.7%) Lower respiratory tract infection  4 (2.5%)  1(0.3%) Pneumonia  5 (3.1%)  2 (0.6%) HLGT: Skin structures and softtissue infections  3 (1.9%)  8 (2.5%) Furuncle  2 (1.2%)  3 (0.9%) HLT:Upper respiratory tract infections  47 (29.2%) 107 (33.1%) Acutesinusitis  2 (1.2%)  5 (1.5%) Nasopharyngitis  24 (14.9%)  53 (16.4%)Pharyngitis  5 (3.1%)  7 (2.2%) Sinusitis  8 (5.0%)  16 (5.0%) Upperrespiratory tract infection  18 (11.2%)  41 (12.7%) HLT: Urinary tractinfections  11 (6.8%)  30 (9.3%) Urinary tract infection  11 (6.8%)  24(7.4%) HLGT: Viral infectious disorders  15 (9.3%)  40 (12.4%) HLGT:Influenzaviral infections  9 (5.6%)  24 (7.4%) Influenza  9 (5.6%)  24(7.4%) HLT: Viral infections NEC  5 (3.1%)  11 (3.4%) Gastroenteritisviral  3 (1.9%)  9 (2.8%) BLOOD AND LYMPHATIC SYSTEM DISORDERS  3 (1.9%) 12 (3.7%) HLGT: Anaemias nonhaemolytic and marrow depression  1 (0.6%) 9 (2.8%) HLT: Anaemias NEC  1 (0.6%)  8 (2.5%) Anaemia  1 (0.6%)  7(2.2%) IMMUNE SYSTEM DISORDERS  3 (1.9%)  5 (1.5%) HLGT: Allergicconditions  3 (1.9%)  5 (1.5%) HLT: Atopic disorders  2 (1.2%)  2 (0.6%)Seasonal allergy  2 (1.2%)  2 (0.6%) ENDOCRINE DISORDERS  2 (1.2%)  3(0.9%) HLGT: Thyroid gland disorders  2 (1.2%)  3 (0.9%) HLT: Thyroidhypofunction disorders  2 (1.2%)  0 Hypothyroidism  2 (1.2%)  0METABOLISM AND NUTRITION DISORDERS  26 (16.1%)  65 (20.1%) HLGT:Appetite and general nutritional disorders  5 (3.1%)  14 (4.3%) HLT:Appetite disorders  5 (3.1%)  14 (4.3%) Decreased appetite  4 (2.5%)  13(4.0%) HLGT: Glucose metabolism disorders (incl diabetes mellitus)  12(7.5%)  27 (8.4%) HLT: Hyperglycaemic conditions NEC  3 (1.9%)  2 (0.6%)Hyperglycaemia  3 (1.9%)  2 (0.6%) HLT: Hypoglycaemic conditions NBC  9(5.6%)  26 (8.0%) Hypoglycaemia  8 (5.0%)  25 (7.7%) HLGT: Lipidmetabolism disorders  6 (3.7%)  8 (2.5%) HLT: Elevated triglycerides  2(1.2%)  3 (0.9%) Hypertriglyceridaemia  2 (1.2%)  3 (0.9%) HLT:Hyperlipidaemias NEC  2 (1.2%)  1 (0.3%) Hyperlipidaemia  2 (1.2%)  1(0.3%) HLT: Lipid metabolism and deposit disorders NEC  1 (0.6%)  5(1.5%) Dyslipidaemia  1 (0.6%)  5 (1.5%) HLGT: Purine and pyrimidinemetabolism disorders  3 (1.9%)  8 (2.5%) HLT: Disorders of purinemetabolism  3 (1.9%)  8 (2.5%) Gout  2 (1.2%)  2 (0.6%) Hyperuricaemia 1 (0.6%)  6 (1.9%) PSYCHIATRIC DISORDERS  14 (8.7%)  31 (9.6%) HLGT:Anxiety disorders and symptoms  4 (2.5%)  9 (2.8%) HLT: Anxiety symptoms 4 (2.5%)  7 (2.2%) Anxiety  2 (1.2%)  5 (1.5%) Stress  2 (1.2%)  2(0.6%) HLGT: Depressed mood disorders and disturbances  7 (4.3%)  13(4.0%) HLT: Depressive disorders  7 (4.3%)  12 (3.7%) Depression  7(4.3%)  12 (3.7%) HLGT: Sleep disorders and disturbances  4 (2.5%)  6(1.9%) HLT: Disturbances in initiating and maintaining sleep  4 (2.5%) 5 (1.5%) Insomnia  4 (2.5%)  5 (1.5%) NERVOUS SYSTEM DISORDERS  44(27.3%)  98 (30.3%) HLGT: Headaches  20 (12.4%)  44 (13.6%) HLT:Headaches NEC  19 (11.8%)  44 (13.6%) Headache  19 (11.8%)  43 (13.3%)HLT: Migraine headaches  3 (1.9%)  0 Migraine  3 (1.9%)  0 HLGT:Movement disorders (incl parkinsonism)  2 (1.2%)  3 (0.9%) HLT: Tremor(excl congenital)  2 (1.2%)  2 (0.6%) Tremor  2 (1.2%)  2 (0.6%) HLGT:Neurological disorders NEC  22 (13.7%)  48 (14.9%) HLT: Neurologicalsigns and symptoms NEC  13 (8.1%)  34 (10.5%) Dizziness  13 (8.1%)  33(10.2%) HLT: Paraesthesias and dysaesthesias  6 (3.7%)  8 (2.5%)Paraesthesia  5 (3.1%)  5 (1.5%) HLT: Sensory abnormalities NEC  5(3.1%)  5 (1.5%) Hypoaesthesia  4 (2.5%)  3 (0.9%) HLGT: Peripheralneuropathies  6 (3.7%)  10 (3.1%) HLT: Peripheral neuropathies NEC  3(1.9%)  4 (1.2%) Neuropathy peripheral  3 (1.9%)  3 (0.9%) HLGT: Spinalcord and nerve root disorders  0  7 (2.2%) HLT: Lumbar spinal cord andnerve root disorders  0  5 (1.5%) Sciatica  0  5 (1.5%) EYE DISORDERS 10 (6.2%)  26 (8.0%) HLGT: Anterior eye structural change, deposit anddegeneration  2 (1.2%)  7 (2.2%) HLT: Cataract conditions  2 (1.2%)  7(2.2%) Cataract  2 (1.2%)  7 (2.2%) HLGT: Ocular infections, irritationsand inflammations  1 (0.6%)  8 (2.5%) HLT: Conjunctival infections,irritations and inflammations  0  6 (1.9%) Conjunctivitis  0  6 (1.9%)HLGT: Retina, choroid and vitreous haemorrhages and vascular  2 (1.2%) 4 (1.2%) disorders HLT: Retinopathies NEC  2 (1.2%)  4 (1.2%) Diabeticretinopathy  1 (0.6%)  4 (1.2%) HLGT: Vision disorders  4 (2.5%)  5(1.5%) HLT: Visual disorders NBC  4 (2.5%)  4 (1.2%) Vision blurred  4(2.5%)  4 (1.2%) EAR AND LABYRINTH DISORDERS  10 (6.2%)  11 (3.4%) HLGT:External ear disorders (excl congenital)  2 (1.2%)  0 HLT: External eardisorders NEC  2 (1.2%)  0 Cerumen impaction  2 (1.2%)  0 HLGT: Innerear and VIIIth cranial nerve disorders  6 (3.7%)  7 (2.2%) HLT: Innerear signs and symptoms  6 (3.7%)  6 (1.9%) Tinnitus  2 (1.2%)  2 (0.6%)Vertigo  4 (2.5%)  3 (0.9%) CARDIAC DISORDERS  11 (6.8%)  22 (6.8%)HLGT: Cardiac arrhythmias  6 (3.7%)  8 (2.5%) HLT: Supraventriculararrhythmias  5 (3.1%)  4 (1.2%) Atrial fibrillation  4 (2.5%)  1 (0.3%)HLGT: Cardiac disorder signs and symptoms  1 (0.6%)  6 (1.9%) HLT:Cardiac signs and symptoms NEC  0  6 (1.9%) Palpitations  0  6 (1.9%)HLGT: Myocardial disorders  2 (1.2%)  0 HLT: Myocardial disorders NEC  2(1.2%)  0 Left ventricular hypertrophy  2 (1.2%)  0 VASCULAR DISORDERS 12 (7.5%)  26 (8.0%) HLGT: Vascular hypertensive disorders  9 (5.6%) 17 (5.3%) HLT: Vascular hypertensive disorders NEC  9 (5.6%)  17 (5.3%)Hypertension  9 (5.6%)  17 (5.3%) RESPIRATORY, THORACIC AND MEDIASTINALDISORDERS  27 (16.8%)  48 (14.9%) HLGT: Bronchial disorders (exclneoplasms)  4 (2.5%)  4 (1.2%) HLT: Bronchospasm and obstruction  4(2.5%)  4 (1.2%) Asthma  2 (1.2%)  2 (0.6%) HLGT: Respiratory disordersNEC  18 (11.2%)  40 (12.4%) HLT: Breathing abnormalities  1 (0.6%)  11(3.4%) Dyspnoea  0  7 (2.2%) HLT: Coughing and associated symptoms  11(6.8%)  18 (5.6%) Cough  11 (6.8%)  18 (5.6%) HLT: Upper respiratorytract signs and symptoms  6 (3.7%)  13 (4.0%) Oropharyngeal pain  3(1.9%)  8 (2.5%) HLGT: Upper respiratory tract disorders (exclinfections)  6 (3.7%)  12 (3.7%) HLT: Nasal congestion and inflammations 2 (1.2%)  5 (1.5%) Nasal congestion  2 (1.2%)  2 (0.6%) HLT: Paranasalsinus disorders (excl infections and neoplasms)  4 (2.5%)  6 (1.9%)Sinus congestion  4 (2.5%)  6 (1.9%) GASTROINTESTINAL DISORDERS  62(38.5%) 156 (48.3%) HLGT: Abdominal hernias and other abdominal wallconditions  4 (2.5%)  6 (1.9%) HLT: Umbilical hernias  1 (0.6%)  4(1.2%) Umbilical hernia  1 (0.6%)  4 (1.2%) HLGT: Benign neoplasmsgastrointestinal  1 (0.6%)  4 (1.2%) HLT: Benign neoplasmsgastrointestinal (excl oral cavity)  1 (0.6%)  4 (1.2%) Colonic polyp  1(0.6%)  4 (1.2%) HLGT: Dental and gingival conditions  3 (1.9%)  11(3.4%) HLT: Dental pain and sensation disorders  3 (1.9%)  4 (1.2%)Toothache  2 (1.2%)  4 (1.2%) HLGT: Gastrointestinal inflammatoryconditions  8 (5.0%)  14 (4.3%) HLT: Gastritis (excl infective)  8(5.0%)  9 (2.8%) Gastritis  8 (5.0%)  9 (2.8%) HLGT: Gastrointestinalmotility and defaecation conditions  27 (16.8%)  53 (16.4%) HLT:Diarrhoea (excl infective)  23 (14.3%)  35 (10.8%) Diarrhoea  23 (14.3%) 35 (10.8%) HLT: Gastrointestinal atonic and hypomotility disorders NEC 6 (3.7%)  21 (6.5%) Constipation  4 (2.5%)  13 (4.0%) Gastrooesophagealreflux disease  3 (1.9%)  10 (3.1%) HLGT: Gastrointestinal signs andsymptoms  42 (26.1%) 113 (35.0%) HLT: Dyspeptic signs and symptoms  6(3.7%)  6 (1.9%) Dyspepsia  6 (3.7%)  5 (1.5%) HLT: Flatulence, bloatingand distension  2 (1.2%)  13 (4.0%) Abdominal distension  1 (0.6%)  5(1.5%) Flatulence  1 (0.6%)  9 (2.8%) HLT: Gastrointestinal andabdominal pains (excl oral and throat)  10 (6.2%)  16 (5.0%) Abdominalpain  6 (3.7%)  7 (2.2%) Abdominal pain lower  3 (1.9%)  2 (0.6%)Abdominal pain upper  3 (1.9%)  6 (1.9%) HLT: Gastrointestinal signs andsymptoms NEC  6 (3.7%)  8 (2.5%) Abdominal discomfort  5 (3.1%)  7(2.2%) HLT: Nausea and vomiting symptoms  25 (15.5%)  91 (28.2%) Nausea 22 (13.7%)  84 (26.0%) Vomiting  8 (5.0%)  26 (8.0%) SKIN ANDSUBCUTANEOUS TISSUE DISORDERS  21 (13.0%)  52 (16.1%) HLGT: Epidermaland dermal conditions  14 (8.7%)  39 (12.1%) HLT: Dermatitis and eczema 6 (3.7%)  14 (4.3%) Dermatitis  2 (1.2%)  4 (1.2%) Dermatitis contact 1 (0.6%)  5 (1.5%) Eczema  2 (1.2%)  3 (0.9%) HLT: Erythemas  2 (1.2%) 1 (0.3%) Erythema  2 (1.2%)  1 (0.3%) HLT: Pruritus NEC  2 (1.2%)  9(2.8%) Pruritus  2 (1.2%)  9 (2.8%) HLT: Rashes, eruptions and exanthemsNEC  3 (1.9%)  15 (4.6%) Rash  3 (1.9%)  13 (4.0%) HLGT: Skin appendageconditions  7 (4.3%)  9 (2.8%) HLT: Alopecias  2 (1.2%)  1 (0.3%)Alopecia  2 (1.2%)  1 (0.3%) HLT: Apocrine and eccrine gland disorders 5 (3.1%)  4 (1.2%) Heat rash  2 (1.2%)  0 Hyperhidrosis  3 (1.9%)  4(1.2%) HLGT: Skin vascular abnormalities  0  5 (1.5%) HLT: Purpura andrelated conditions  0  5 (1.5%) Ecchymosis  0  4 (1.2%) MUSCULOSKELETALAND CONNECTIVE TISSUE DISORDERS  43 (26.7%)  99 (30.7%) HLGT: Jointdisorders  17 (10.6%)  41 (12.7%) HLT: Joint related disorders NEC  3(1.9%)  4 (1.2%) Rotator cuff syndrome  2 (1.2%)  2 (0.6%) HLT: Jointrelated signs and symptoms  11 (6.8%)  25 (7.7%) Arthralgia  11 (6.8%) 24 (7.4%) HLT: Osteoarthropathies  5 (3.1%)  11 (3.4%) Osteoarthritis 4 (2.5%)  10 (3.1%) HLGT: Muscle disorders  11 (6.8%)  18 (5.6%) HLT:Muscle pains  3 (1.9%)  7 (2.2%) Myalgia  3 (1.9%)  6 (1.9%) HLT: Musclerelated signs and symptoms NEC  8 (5.0%)  9 (2.8%) Muscle spasms  8(5.0%)  9 (2.8%) HLGT: Musculoskeletal and connective tissue deformities(incl intervertebral disc disorders)  4 (2.5%)  2 (0.6%) HLT:Intervertebral disc disorders NEC  2 (1.2%)  2 (0.6%) Intervertebraldisc protrusion  2 (1.2%)  2 (0.6%) HLGT: Musculoskeletal and connectivetissue disorders NEC  24 (14.9%)  54 (16.7%) HLT: Musculoskeletal andconnective tissue pain and discomfort  22 (13.7%)  51 (15.8%) Back pain 14 (8.7%)  22 (6.8%) Flank pain  2 (1.2%)  5 (1.5%) Musculoskeletalpain  4 (2.5%)  9 (2.8%) Neck pain  3 (1.9%)  4 (1.2%) Pain in extremity 8 (5.0%)  15 (4.6%) HLT: Musculoskeletal and connective tissue signsand symptoms NEC  2 (1.2%)  2 (0.6%) Musculoskeletal stiffness  2 (1.2%) 2 (0.6%) HLGT: Synovial and bursal disorders  2 (1.2%)  8 (2.5%) HLT:Bursal disorders  1 (0.6%)  6 (1.9%) Bursitis  1 (0.6%)  6 (1.9%) RENALAND URINARY DISORDERS  10 (6.2%)  24 (7.4%) HLGT: Urolithiases  2 (1.2%) 8 (2.5%) HLT: Renal lithiasis  2 (1.2%)  8 (2.5%) Nephrolithiasis  2(1.2%)  7 (2.2%) GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 32 (19.9%)  84 (26.0%) HLGT: Administration site reactions  7 (4.3%) 23 (7.1%) HLT: Injection site reactions  7 (4.3%)  22 (6.8%) Injectionsite erythema  0  5 (1.5%) Injection site haematoma  3 (1.9%)  8 (2.5%)Injection site pain  4 (2.5%)  5 (1.5%) Injection site pruritus  0  4(1.2%) Injection site reaction  1 (0.6%)  4 (1.2%) HLGT: Bodytemperature conditions  3 (1.9%)  6 (1.9%) HLT: Febrile disorders  2(1.2%)  6 (1.9%) Pyrexia  2 (1.2%)  6 (1.9%) HLGT: General systemdisorders NEC  24 (14.9%)  65 (20.1%) HLT: Asthenic conditions  5 (3.1%) 30 (9.3%) Asthenia  2 (1.2%)  10 (3.1%) Fatigue  3 (1.9%)  21 (6.5%)HLT: General signs and symptoms NEC  1 (0.6%)  7 (2.2%) Influenza likeillness  0  4 (1.2%) HLT: Oedema NEC  12 (7.5%)  23 (7.1%) Oedema  3(1.9%)  6 (1.9%) Oedema peripheral  9 (5.6%)  17 (5.3%) HLT: Pain anddiscomfort NEC  7 (4.3%)  11 (3.4%) Chest discomfort  2 (1.2%)  1 (0.3%)Non-cardiac chest pain  0  5 (1.5%) Pain  5 (3.1%)  3 (0.9%) HLGT:Tissue disorders NEC  3 (1.9%)  2 (0.6%) HLT: Mass conditions NEC  2(1.2%)  2 (0.6%) Cyst  2 (1.2%)  1 (0.3%) INVESTIGATIONS  20 (12.4%)  40(12.4%) HLGT: Endocrine investigations (incl sex hormones)  7 (4.3%)  10(3.1%) HLT: Gastrointestinal, pancreatic and APUD hormone analyses  6(3.7%)  10 (3.1%) Blood calcitonin increased  6 (3.7%)  10 (3.1%) HLGT:Gastrointestinal investigations  4 (2.5%)  6 (1.9%) HLT: Digestiveenzymes  3 (1.9%)  6 (1.9%) Blood amylase increased  1 (0.6%)  4 (1.2%)Lipase increased  3 (1.9%)  6 (1.9%) HLGT: Lipid analyses  1 (0.6%)  4(1.2%) HLT: Triglyceride analyses  1 (0.6%)  4 (1.2%) Bloodtriglycerides increased  1 (0.6%)  4 (1.2%) HLGT: Metabolic, nutritionaland blood gas investigations  6 (3.7%)  7 (2.2%) HLT: Carbohydratetolerance analyses (incl diabetes)  5 (3.1%)  5 (1.5%) Blood glucosedecreased  4 (2.5%)  4 (1.2%) HLGT: Physical examination topics  3(1.9%)  7 (2.2%) HLT: Physical examination procedures  3 (1.9%)  7(2.2%) Weight increased  2 (1.2%)  5 (1.5%) INJURY, POISONING ANDPROCEDURAL COMPLICATIONS  20 (12.4%)  60 (18.6%) HLGT: Bone and jointinjuries  6 (3.7%)  26 (8.0%) HLT: Limb injuries NEC find traumaticamputation)  5 (3.1%)  17 (5.3%) Joint sprain  2 (1.2%)  6 (1.9%) Limbinjury  0  9 (2.8%) Meniscus lesion  3 (1.9%)  1 (0.3%) HLGT: InjuriesNEC  12 (7.5%)  41 (12.7%) HLT: Muscle, tendon and ligament injuries  3(1.9%)  7 (2.2%) Muscle strain  3 (1.9%)  4 (1.2%) HLT: Non-sitespecific injuries NEC  4 (2.5%)  17 (5.3%) Fall  1 (0.6%)  5 (1.5%) Roadtraffic accident  2 (1.2%)  3 (0.9%) HLT: Site specific injuries NEC  2(1.2%)  3 (0.9%) Tooth fracture  2 (1.2%)  1 (0.3%) HLT: Skin injuriesNEC  5 (3.1%)  17 (5.3%) Contusion  5 (3.1%)  12 (3.7%) Excoriation  0 4 (1.2%) SURGICAL AND MEDICAL PROCEDURES  5 (3.1%)  6 (1.9%) HLGT: Headand neck therapeutic procedures  2 (1.2%)  2 (0.6%) HLT: Paranasaltherapeutic procedures  2 (1.2%)  1 (0.3%) Sinus operation  2 (1.2%)  1(0.3%) HLGT: Vascular therapeutic procedures  2 (1.2%)  2 (0.6%) HLGT:Arterial therapeutic procedures (excl aortic)  2 (1.2%)  2 (0.6%)Coronary artery bypass  2 (1.2%)  0 TEAE: Treatment Emergent AdverseEvent, SOC: System Organ Class, HLGT: High Level Group Term, HLT: HighLevel Term, PT: Preferred Term. MedDRA version: 14.0. n (%) = number andpercentage of patients with at least one TEAE. Note: on-treatment periodof the whole study = the time from the first dose of double-blind studymedication up to 3 days after the last dose administration. Table sortedby SOC internationally agreed order and HLGT, HLT, PT by alphabeticorder. Only SOC with at least one PT ≥ 1% in at least one group arepresented.

1. A method for improving glycemic control in a patient with type 2diabetes not adequately controlled by treatment with a glitazone, themethod comprising administering to the patient in need thereof apharmaceutical combination comprising: (a) insulin glargine at a dose of15 U/day to 60 U/day; (b) lixisenatide at a dose of 10 μg/day to 20μg/day, and (c) a glitazone at a dose of 10 mg/day to 60 mg/day.
 2. Themethod of claim 1, wherein the pharmaceutical combination furthercomprises: (d) metformin at a dose of 1.0 g/day to 1.5 g/day.
 3. Themethod of claim 1, wherein the patient is inadequately controlled bytreatment with a combination of glitazone and metformin.
 4. The methodof claim 1, wherein the glitazone is pioglitazone.